Andreia Zago Chignalia
- Assistant Professor
- Member of the Graduate Faculty
- Adjunct Research Assistant Professor, Pharmacology and Toxicology
- Assistant Professor, Clinical Translational Sciences
- Assistant Research Professor, Physiology - (Research Series Track)
- (520) 626-7221
- AHSC, Rm. 4401
- Tucson, AZ 85724
- azchignalia@arizona.edu
Awards
- FUTURRE Award
- Doris Duke Charitable Foundation, Fall 2022
- New Investigator Award
- (1) Novel Research Project Award in the Area of Cardiovascular Disease and Medicine Ralph and Shirley Morgan(2) Congenital Heart Disease Research AwardWilliam “Billy” Gieszl, Fall 2022
- UAHS Career Development Award
- University of Arizona, Spring 2021
Interests
Research
My laboratory has focused on doing translational research using animal models of diseases. I am interested in giving a next step towards clinical research adding human samples to our studies.
Teaching
I am interested in affiliating to a graduation program so I can mentor PhD and master degree students. I am also interested in assisting the department on getting residents interested in research and contributing to their research training.
Courses
2024-25 Courses
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Individualized Science Writing
CTS 585 (Fall 2024) -
Introduction to Pharmacology
PCOL 501 (Fall 2024) -
Introduction to Pharmacology
PHSC 501 (Fall 2024) -
Senior Capstone
BIOC 498 (Fall 2024)
2023-24 Courses
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Introduction to Pharmacology
PCOL 501 (Fall 2023)
2022-23 Courses
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Independent Study
PSIO 399 (Spring 2023) -
Independent Study
PSIO 399 (Fall 2022) -
Independent Study
PSIO 499 (Fall 2022) -
Introduction to Pharmacology
PCOL 501 (Fall 2022) -
Introduction to Pharmacology
PHSC 501 (Fall 2022)
2021-22 Courses
-
Introduction to Pharmacology
PCOL 501 (Fall 2021) -
Introduction to Pharmacology
PHSC 501 (Fall 2021)
2020-21 Courses
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Introduction to Pharmacology
PCOL 501 (Fall 2020) -
Introduction to Pharmacology
PHSC 501 (Fall 2020)
2019-20 Courses
-
Honors Thesis
PSIO 498H (Spring 2020) -
Honors Thesis
PSIO 498H (Fall 2019)
Scholarly Contributions
Chapters
- Mortazavi, C., Hoyt, J., Patel, A., & Chignalia, A. Z. (2023). The glycocalyx and calcium dynamics in endothelial cells. In Current Topics in Membranes. doi:10.1016/bs.ctm.2023.02.002.
- Touyz, R. M., Chignalia, A. Z., & Sedeek, M. (2010). Reactive Oxygen Species, Oxidative Stress, and Hypertension. In Studies in Cardiovascular Disorders. Humana Press, Totowa, NJ. doi:10.1007/978-1-60761-600-9_15More infoReactive oxygen species (ROS) influence many physiological processes including host defense, hormone biosynthesis, fertilization and cellular signaling. Increased ROS production has been implicated in various chronic diseases, including hypertension, atherosclerosis, diabetes and kidney disease. Oxidative stress may be both a cause and a consequence of hypertension. Although oxidative injury may not be the sole etiology, it amplifies blood pressure elevation in the presence of other prohypertensive factors, such as salt loading, activation of the renin-angiotensin system and sympathetic hyperactivity. Oxidative stress is a multisystem phenomenon in hypertension and involves the heart, kidneys, nervous system, and vessels. Compelling evidence indicates the importance of the vasculature in the pathophysiology of hypertension, and therefore much emphasis has been placed on the (patho)biology of ROS in the vascular system. A major source for cardiovascular and renal ROS is a family of nonphagocytic NAD(P)H oxidases, including the prototypic Nox2 homologue-based NAD(P)H oxidase, as well as other NAD(P)H oxidases, such as Nox1 and Nox4. Other possible sources include mitochondrial electron transport enzymes, xanthine oxidase, cyclooxygenase, lipoxygenase, and uncoupled nitric oxide synthase (NOS). NAD(P)H oxidase-derived ROS is important in regulating endothelial function and vascular tone, and oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis, and rarefaction, important processes involved in vascular remodeling in hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against nonphagocytic NAD(P)H oxidase to decrease ROS generation and/or strategies to increase nitric oxide (NO) availability and antioxidants may be useful in minimizing vascular injury and thereby prevent or regress target organ damage associated with hypertension.
Journals/Publications
- Chignalia, A. Z. (2023).
Abstract P2048: New Insights Into The Role Of The Glycocalyx Components In Heart Failure Induced By Pressure Overload.
. Circulation Research, 133(Suppl_1). doi:10.1161/res.133.suppl_1.p2048 - Chignalia, A. Z. (2023).
The Pulmonary Endothelial Glycocalyx Modifications in Glypican 1 Knockout Mice Do Not Affect Lung Endothelial Function in Physiological Conditions
. International Journal of Molecular Sciences, 24(19), 14568. doi:10.3390/ijms241914568 - Chignalia, A. Z. (2023). Novel avenues to control blood pressure: targeting the renal lymphatic system. Clinical Sciences. doi:10.1042/CS20220775.
- Fancher, I. S., & Chignalia, A. Z. (2023). Preface. Current topics in membranes, 91, ix-x.
- Chignalia, A. Z. (2022).
Abstract 15352: Lung Endothelial Transport in Glypican 1 Knockout Mice
. Circulation, 146(Suppl_1). doi:10.1161/circ.146.suppl_1.15352 - Chignalia, A. Z., & Thota, L. N. (2022). The role of the glypican and syndecan families of heparan sulfate proteoglycans in cardiovascular function and disease. American Journal of Physiology-cell Physiology. doi:10.1152/ajpcell.00018.2022More infoHeparan sulfate proteoglycans (HSPGs) are proteoglycans formed by a core protein to which one or multiple heparan sulfate chains are covalently bound. They are ubiquitously expressed in cellular surfaces and can be found in the extracellular matrix and secretory vesicles. The cellular effects of HSPGs comprehend multiple functionalities that include 1) the interaction with other membrane surface proteins to act as a substrate for cellular migration, 2) acting as a binding site for circulating molecules, 3) to have a receptor role for proteases, 4) to act as a coreceptor that can provide finetuning of growth factor receptor activity threshold, and 5) to activate intracellular signaling pathways (Sarrazin S, Lamanna WC, Esko JD. Cold Spring Harb Perspect Biol 3: a004952, 2011). Among the different families of HSPGs, the syndecan and glypican families of HSPGs have gained increased attention in relation to their effects on cardiovascular cells and potential role in disease progression. In this review, we will summarize the effects of syndecan and glypican homologs on the different cardiovascular cell types and discuss their contribution to common processes found in cardiovascular diseases (inflammation, hypertrophy, and vascular remodeling) as well as their potential role in the development and progression of specific diseases including hypertension, heart failure, and atherosclerosis.
- Souza, D. S., Chignalia, A. Z., & De Souza, J. L. (2022). Modulation of cardiac voltage-activated K+ currents by glypican 1 heparan sulfate proteoglycan. Life Sciences.
- Black, S. M., Chignalia, A. Z., Carvalho-de-Souza, J., & Zemskov, E. (2021). Abstract 13551: RhoA Mediates Pressure-Induced Endothelial Hyperpermeability. Circulation, 144(Suppl_1). doi:10.1161/circ.144.suppl_1.13551
- Potje, S. R., Isbatan, A., Tostes, R. C., Bendhack, L. M., Dull, R. O., Carvalho-de-Souza, J. L., & Chignalia, A. Z. (2021). Glypican 1 and syndecan 1 differently regulate noradrenergic hypertension development: Focus on IP3R and calcium. Pharmacological research, 172, 105813.More infoVascular dysfunction is a checkpoint to the development of hypertension. Heparan sulfate proteoglycans (HSPG) participate in nitric oxide (NO) and calcium signaling, key regulators of vascular function. The relationship between HSPG-mediated NO and calcium signaling and vascular dysfunction has not been explored. Likewise, the role of HSPG on the control of systemic blood arterial pressure is unknown. Herein, we sought to determine if the HSPG syndecan 1 and glypican 1 control systemic blood pressure and the progression of hypertension.
- Chignalia, A. Z., Weinberg, G., & Dull, R. O. (2020). Norepinephrine Induces Lung Microvascular Endothelial Cell Death by NADPH Oxidase-Dependent Activation of Caspase-3. Oxidative medicine and cellular longevity, 2020, 2563764.More infoNorepinephrine (NE) is the naturally occurring adrenergic agonist that is released in response to hypotension, and it is routinely administered in clinical settings to treat moderate to severe hypotension that may occur during general anesthesia and shock states. Although NE has incontestable beneficial effects on blood pressure maintenance during hypotensive conditions, deleterious effects of NE on endothelial cell function may occur. In particular, the role of reactive oxygen species (ROS) and NADPH oxidase (Nox) on the deleterious effects of NE on endothelial cell function have not been fully elucidated. Therefore, we investigated the effects of NE on ROS production in rat lung microvascular endothelial cells (RLMEC) and its contribution to cell death. RLMEC were treated with NE (5 ng/mL) for 24 hours and ROS production was assessed by CellROX and DCFDA fluorescence. Nox activity was assessed by NADPH-stimulated ROS production in isolated membranes and phosphorylation of p47phox; cell death was assessed by flow cytometry and DNA fragmentation. Caspase activation was assessed by fluorescent microscopy. Nox1, Nox2, and Nox4 mRNA expression was assessed by real-time PCR. NE increased ROS production, Nox activity, p47phox phosphorylation, Nox2 and Nox4 mRNA content, caspase-3 activation, and RLMEC death. Phentolamine, an -adrenoreceptor antagonist, inhibited NE-induced ROS production and Nox activity and partly inhibited cell death while -blockade had no effect. Apocynin and PEGSOD inhibited NE-induced caspase-3 activation and cell death while direct inhibition of caspase-3 abrogated NE-induced cell death. PEG-CAT inhibited NE-induced cell death but not caspase-3 activation. Collectively, these results indicate that NE induces RLMEC death via activation of Nox by -adrenergic signaling and caspase-3-dependent pathways. NE has deleterious effects on RLMECs that may be important to its long-term therapeutic use.
- Dull, R. O., & Chignalia, A. Z. (2020). The Glycocalyx and Pressure-Dependent Transcellular Albumin Transport. Cardiovascular engineering and technology, 11(6), 655-662.More infoAcute increases in hydrostatic pressure activate endothelial signaling pathways that modulate barrier function and vascular permeability. We investigated the role the glycocalyx and established mechanotransduction pathways in pressure-induced albumin transport across rat lung microvascular endothelial cells.
- Dull, R. O., Chignalia, A. Z., Isbatan, A., Dull, R. O., Chignalia, A. Z., & Black, S. M. (2020). Glypican‐1 Is a Trigger for Pulmonary Edema Development During Acute Heart Failure. The FASEB Journal, 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.02749
- Garcia, R., , ., Dull, R. O., Chignalia, A. Z., Carvalho-de-souza, J. L., & Cannon, M. (2020). Glypican‐1 Plays a Cardiac Protective Effect During Heart Failure Induced by Pressure Overload. The FASEB Journal, 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.05845
- Hansen, M., Garcia, R., Dull, R. O., Chignalia, A. Z., & Carvalho-de-souza, J. L. (2020). Glypican‐1 and Remodeling Cardiac Hypertrophy.. The FASEB Journal, 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.05765
- Patel, M., Chignalia, A. Z., Isbatan, A., Bommakanti, N., & Dull, R. O. (2019). Ropivacaine inhibits pressure-induced lung endothelial hyperpermeability in models of acute hypertension. Life sciences, 222, 22-28.More infoIncreases in hydrostatic pressure results in endothelial hyperpermeability via eNOS-dependent pathways. Ropivacaine is known to inhibit eNOS activation and to attenuate lung injury. Herein, we sought to determine if ropivacaine regulates pressure-induced lung endothelial hyperpermeability.
- Potje, S. R., Grando, M. D., Chignalia, A. Z., Antoniali, C., & Bendhack, L. M. (2019). Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production. Scientific reports, 9(1), 6696.More infoCaveolae are plasma membrane invaginations enriched with high cholesterol and sphingolipid content; they also contain caveolin proteins in their structure. Endothelial nitric oxide synthase (eNOS), an enzyme that synthesizes nitric oxide (NO) by converting L-arginine to L-citrulline, is highly concentrated in plasma membrane caveolae. Hypertension is associated with decreased NO production and impaired endothelium-dependent relaxation. Understanding the molecular mechanisms that follow hypertension is important. For this study, we hypothesized that spontaneously hypertensive rat (SHR) vessels should have a smaller number of caveolae, and that the caveolae structure should be disrupted in these vessels. This should impair the eNOS function and diminish NO bioavailability. Therefore, we aimed to investigate caveolae integrity and density in SHR aortas and mesenteric arteries and the role played by caveolae in endothelium-dependent relaxation. We have been able to show the presence of caveolae-like structures in SHR aortas and mesenteric arteries. Increased phenylephrine-induced contractile response after treatment with dextrin was related to lower NO release. In addition, impaired acetylcholine-induced endothelium-dependent relaxation could be related to decreased caveolae density in SHR vessels. The most important finding of this study was that cholesterol depletion with dextrin induced eNOS phosphorylation at Serine (Ser) and boosted reactive oxygen species (ROS) production in normotensive rat and SHR vessels, which suggested eNOS uncoupling. Dextrin plus L-NAME or BH decreased ROS production in aorta and mesenteric arteries supernatant's of both SHR and normotensive groups. Human umbilical vein endothelial cells (HUVECs) treated with dextrin confirmed eNOS uncoupling, as verified by the reduced eNOS dimer/monomer ratio. BH, L-arginine, or BH plus L-arginine inhibited eNOS monomerization. All these results showed that caveolae structure and integrity are essential for endothelium-dependent relaxation. Additionally, a smaller number of caveolae is associated with hypertension. Finally, caveolae disruption promotes eNOS uncoupling in normotensive and hypertensive rat vessels and in HUVECs.
- Chignalia, A. Z., Isbatan, A., Patel, M., Ripper, R., Sharlin, J., Shosfy, J., Borlaug, B. A., & Dull, R. O. (2018). Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure.. Bioscience reports, 38(6). doi:10.1042/bsr20181239More infoAims: Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension.Methods and results: Male Sprague-Dawley rats were anesthetized and mechanically ventilated. Acute hypertension was induced by norepinephrine (NE) infusion and resulted in an increase in LVEDP and pulmonary artery pressure (Ppa) that were associated with a rapid fall in PaO2, and increases in lung wet/dry ratio and injury scores. Heart failure (HF) lungs showed increased nitrotyrosine content and ROS levels. L-NAME pretreatment mitigated the development of PE and reduced lung ROS concentrations to sham levels. Apocynin (Apo) pretreatment inhibited PE. Addition of tetrahydrobiopterin (BH4) to AHF rats lung lysates and pretreatment of AHF rats with folic acid (FA) prevented ROS production indicating endothelial NOS (eNOS) uncoupling.Conclusion: Pressure-dependent NOS activation leads to acute endothelial hyperpermeability and rapid PE by an increase in NO and ROS in a model of AHF. Acute increases in pulmonary vascular pressure, without NOS activation, was insufficient to cause significant PE. These results suggest a clinically relevant role of endothelial mechanotransduction in the pathogenesis of AHF and further highlights the concept of active barrier failure in AHF. Therapies targetting the prevention or reversal of endothelial hyperpermeability may be a novel therapeutic strategy in AHF.
- Isbatan, A., Hu, G., Dull, R. O., Chignalia, A. Z., & Borlaug, B. A. (2018). Glypican-1 mediates endothelial hyperpermeability in a model of acute heart failure. Free Radical Biology and Medicine, 128, S23. doi:10.1016/j.freeradbiomed.2018.10.009More infoThe lungs are active participants in heart failure (HF). Increases in LVEDP augments pulmonary capillary pressure (PCP) that causes fluid filtration resulting in dyspnea and, ultimately, frank pulmonary edema (PE). The increase in PCP does not translate to the severity of dyspnea indicating that more than Starling Forces contribute to the clinical manifestation of HF. Acute increases in PCP activate glycocalyx-dependent mechanotransduction resulting in oxidative stress, eNOS activation and endothelial hyperpermeability. Herein we investigated if glypican-1 (Gpc-1) contributes to pressure-dependent hyperpermeability and PE in a model of acute HF. The isolated perfused lung preparation was used to simulate acute HF in male CD-1 (wild type, WT) and glypican-1 knockout (Gpc-1-/-) mice. Control experiments were done setting left atria pressure (PLA) at 3cm H2O for 10min; acute HF was simulated by setting PLA at 10cm H2O for 10min. Lung edema was assessed by wet-to-dry ratio (W/D); reactive oxygen species (ROS) production and eNOS activation were assessed by lucigenin chemiluminescence, DHE fluorescence and immunoblotting, respectively. WT and Gpc-1-/- mice had similar increase in PA pressure (from 8 to 10 mmHg). Deletion of Gpc-1 protected mice from pressure-induced PE (W/D [acute HF and control]), respectively in WT: 7.3±0.3 vs 4.9±0.3 and in Gpc-1-/-: 4.8±0.3 vs 4.8±0.2), prevented pressure-dependent increase in ROS production in isolated membrane fraction and in total lung homogenates (15% and 80% increase in WT). eNOS activity was increased in WT (2-fold) and decreased in Gpc-1-/- (0.5 fold) during acute HF. L-NIO inhibited edema development in WT (W/D 6.9±0.2 and 5.1±0.1 in WT and L-NIO-perfused WT, respectively). Perfusion of Gpc-1-/- lungs with NOC9 restored the response to pressure and edema development (W/D 5.1±0.1 and 5.78±0.2 in Gpc1-/- and NOC9-perfused Gpc-1-/-, respectively). Collectively, these results suggest that Gpc-1 is required for pressure-induced endothelial hyperpermeability and PE in a model of acute HF.
- Phillips, S. A., Levitan, I., Isbatan, A., Fancher, I. S., Dull, R. O., & Chignalia, A. Z. (2018). Abstract 16551: Shear-Induced Kir2.1 Channel Activation is Mediated Through Interactions With Syndecan-1. Circulation.More infoInwardly rectifying K+ (Kir) channels are known to be sensitive to flow and proposed to play a major role in endothelial mechanotransduction. We recently identified a critical role for endothelial ...
- Potje, S. R., Grando, M. D., Antoniali, C., Bendhack, L. M., & Chignalia, A. Z. (2018). Disrupting caveolae promotes eNOS uncoupling and ROS production. Free Radical Biology and Medicine, 128, S36-S37. doi:10.1016/j.freeradbiomed.2018.10.049More infoCaveolae are plasma membrane invaginations enriched with high cholesterol and sphingolipid content; they also contain caveolin proteins in their structure. Endothelial nitric oxide synthase (eNOS) is highly concentrated in plasma membrane caveolae. Hypertension is associated with decreased nitric oxide (NO) production and impaired endothelium-dependent relaxation. Therefore, we aimed to investigate caveola integrity and density in SHR aortas and mesenteric arteries and the role played by caveolae in endothelium-dependent relaxation. We showed the presence of caveola-like structures in SHR aortas and mesenteric arteries. Increased phenylephrine-induced contractile response after treatment with dextrin was related to lower NO release. In addition, impaired acetylcholine-induced endothelium-dependent relaxation could be related to decreased caveola density in SHR vessels. Cholesterol depletion with dextrin induced eNOS phosphorylation at Serine1177 (Ser1177) and boosted reactive oxygen species (ROS) production in Wistar rat and SHR vessels, which suggested eNOS uncoupling. Human umbilical vein endothelial cells (HUVECs) treated with dextrin confirmed eNOS uncoupling, as verified by the reduced eNOS dimer/monomer ratio. BH4, L-arginine, or BH4 plus L-arginine inhibited eNOS monomerization. The results showed that caveola structure and its integrity are essential for endothelium-dependent relaxation. Additionally, a smaller number of caveolae is associated with hypertension. Finally, caveola disruption promotes eNOS uncoupling in normotensive and hypertensive rat vessels and in HUVECs.
- Potje, S. R., Katiki, A., Isbatan, A., Bendhack, L. M., Dull, R. O., & Chignalia, A. Z. (2018). Heparan sulfate proteoglycans regulate aortic response to vasoactive agents. Free Radical Biology and Medicine, 128, S36. doi:10.1016/j.freeradbiomed.2018.10.048More infoThe endothelial glycocalyx is known to regulate vascular function by sensing mechanical forces and by acting as a barrier to solute and protein transport. Its role on the regulation of vascular tone and blood pressure is incipient. Herein we sought to investigate if the genetic deletion of syndecan-1 (Sdc-1) and glypican-1 (Gpc-1) alters vascular reactivity. Male CD-1, C57BL/6, Sdc-1 knockout (Sdc-1-/-) and Gpc-1 knockout (Gpc-1-/-) mice were used. Vascular response to phenylephrine (PE, 1 nM to 0.1 µM), acetylcholine (Ach, 10 µM to 10 mM), angiotensin II (Ang II, 1 nM to 0.1 µM) was assessed in aortic rings with endothelium. The expression of p-eNOS Ser1177, eNOS, p-Akt Ser473, Akt, p-Cav-1 Tyr14 and Cav-1 were analyzed by immunoblotting. Aortic rings from Gpc-1-/- mice showed an increased maximum response to Ang II (0.21g) and preserved response to PE (0.30g) when compared to CD1 control (PE: 0.28g; Ang: 0.14g). Aortic rings from Sdc-1-/- mice showed an increased maximum response to PE (0.29g) and a decreased maximum response to Ang II (0.04g) when compared to C57BL/6 (PE: 0.13g; Ang: 0.08g). Both strains showed impaired endothelium-dependent relaxation and decreased eNOS and AKT activity. Only Sdc-1-/- showed decreased eNOS expression when compared to respective control. Gpc-1-/- showed increased p-Cav-1 Tyr14 and Cav-1 when compared to CD-1 mice. Sdc-1-/- mice had decreased p-Cav-1 Tyr14 and Cav-1 when compared to C57BL/6 mice. In addition, ROS were decreased in both Sdc-1-/- (4253.00 AU) and Gpc-1-/- (4993.20 AU) mice when compared to C57BL/6 (19166.40 AU) and CD-1 (15584.60 AU) controls. Deletion of heparan sulfate proteoglycans alter the vascular response to specific vasoactive agents by potentially redox-sensitive mechanisms. The endothelial glycocalyx may be a primary regulator of vascular tone.
- Bommakanti, N., Isbatan, A., Bavishi, A., Dharmavaram, G., Chignalia, A. Z., & Dull, R. O. (2017). Hypercapnic acidosis attenuates pressure-dependent increase in whole-lung filtration coefficient (Kf).. Pulmonary circulation, 7(3), 719-726. doi:10.1177/2045893217724414More infoHypercapnic acidosis (HCA) has beneficial effects in experimental models of lung injury by attenuating inflammation and decreasing pulmonary edema. However, HCA increases pulmonary vascular pressure that will increase fluid filtration and worsen edema development. To reconcile these disparate effects, we tested the hypothesis that HCA inhibits endothelial mechanotransduction and protects against pressure-dependent increases in the whole lung filtration coefficient (Kf). Isolated perfused rat lung preparation was used to measure whole lung filtration coefficient (Kf) at two levels of left atrial pressure (PLA = 7.5 versus 15 cm H2O) and at low tidal volume (LVt) versus standard tidal volume (STVt) ventilation. The ratio of Kf2/Kf1 was used as the index of whole lung permeability. Double occlusion pressure, pulmonary artery pressure, pulmonary capillary pressures, and zonal characteristics (ZC) were measured to assess effects of HCA on hemodynamics and their relationship to Kf2/Kf1. An increase in PLA2 from 7.5 to 15 cm H2O resulted in a 4.9-fold increase in Kf2/Kf1 during LVt and a 4.8-fold increase during STVt. During LVt, HCA reduced Kf2/Kf1 by 2.7-fold and reduced STVt Kf2/Kf1 by 5.2-fold. Analysis of pulmonary hemodynamics revealed no significant differences in filtration forces in response to HCA. HCA interferes with lung vascular mechanotransduction and prevents pressure-dependent increases in whole lung filtration coefficient. These results contribute to a further understanding of the lung protective effects of HCA.
- Changyaleket, B., Deliu, Z., Chignalia, A. Z., & Feinstein, D. L. (2017). Heparanase: Potential roles in multiple sclerosis.. Journal of neuroimmunology, 310, 72-81. doi:10.1016/j.jneuroim.2017.07.001More infoHeparanase is a heparan sulfate degrading enzyme that cleaves heparan sulfate (HS) chains present on HS proteoglycans (HSPGs), and has been well characterized for its roles in tumor metastasis and inflammation. However, heparanase is emerging as a contributing factor in the genesis and severity of a variety of neurodegenerative diseases and conditions. This is in part due to the wide variety of HSPGs on which the presence or absence of HS moieties dictates protein function. This includes growth factors, chemokines, cytokines, as well as components of the extracellular matrix (ECM) which in turn regulate leukocyte infiltration into the CNS. Roles for heparanase in stroke, Alzheimer's disease, and glioma growth have been described; roles for heparanase in other disease such as multiple sclerosis (MS) are less well established. However, given its known roles in inflammation and leukocyte infiltration, it is likely that heparanase also contributes to MS pathology. In this review, we will briefly summarize what is known about heparanase roles in the CNS, and speculate as to its potential role in regulating disease progression in MS and its animal model EAE (experimental autoimmune encephalitis), which may justify testing of heparanase inhibitors for MS treatment.
- Chignalia, A. Z., Yetimakman, F., Christiaans, S. C., Unal, S., Bayrakci, B., Wagener, B. M., Russell, R. T., Kerby, J. D., Pittet, J., & Dull, R. O. (2016). THE GLYCOCALYX AND TRAUMA: A REVIEW.. Shock (Augusta, Ga.), 45(4), 338-48. doi:10.1097/shk.0000000000000513More infoIn the United States trauma is the leading cause of mortality among those under the age of 45, claiming approximately 192,000 lives each year. Significant personal disability, lost productivity, and long-term healthcare needs are common and contribute 580 billion dollars in economic impact each year. Improving resuscitation strategies and the early acute care of trauma patients has the potential to reduce the pathological sequelae of combined exuberant inflammation and immune suppression that can co-exist, or occur temporally, and adversely affect outcomes. The endothelial and epithelial glycocalyx has emerged as an important participant in both inflammation and immunomodulation. Constituents of the glycocalyx have been used as biomarkers of injury severity and have the potential to be target(s) for therapeutic interventions aimed at immune modulation. In this review, we provide a contemporary understanding of the physiologic structure and function of the glycocalyx and its role in traumatic injury with a particular emphasis on lung injury.
- Chignalia, A. Z., Oliveira, M. A., Debbas, V., Dull, R. O., Laurindo, F. R., Touyz, R. M., Fortes, Z. B., Tostes, R. C., & Carvalho, M. H. (2015). Testosterone induces leucocyte migration by NADPH oxidase-driven ROS- and COX2-dependent mechanisms.. Clinical science (London, England : 1979), 129(1), 39-48. doi:10.1042/cs20140548More infoThe mechanisms whereby testosterone increases cardiovascular risk are not clarified. However, oxidative stress and inflammation seem to be determinants. Herein, we sought to determine whether exogenous testosterone, at physiological levels, induces leucocyte migration, a central feature in immune and inflammatory responses and the mediating mechanisms. We hypothesized that testosterone induces leucocyte migration via NADPH oxidase (NADPHox)-driven reactive oxygen species (ROS) and cyclooxygenase (COX)-dependent mechanisms. Sixteen-week-old Wistar rats received an intraperitoneal injection (5 ml) of either testosterone (10(-7) mol/l) or saline. Rats were pre-treated with 5 ml of sodium salicylate (SS, non-selective COX inhibitor, 1.25 × 10(-3) mol/l, 1 h prior to testosterone or saline), flutamide (androgen receptor antagonist, 10(-5) mol/l), apocynin (NADPHox inhibitor, 3 × 10(-4) mol/l), N-[2-Cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS398, COX2 inhibitor, 10(-4) mol/l) or saline, 4 h before testosterone or saline administration. Leucocyte migration was assessed 24 h after testosterone administration by intravital microscopy of the mesenteric bed. Serum levels of testosterone were measured by radioimmunoassay. NADPHox activity was assessed in membrane fractions of the mesenteric bed by dihydroethidium (DHE) fluorescence and in isolated vascular smooth muscle cells (VSMC) by HPLC. NADPHox subunits and VCAM (vascular cell adhesion molecule) expression were determined by immunoblotting. Testosterone administration did not change serum levels of endogenous testosterone, but increased venular leucocyte migration to the adventia, NADPHox activity and expression (P < 0.05). These effects were blocked by flutamide. SS inhibited testosterone-induced leucocyte migration (P
- Chignalia, A. Z., Vogel, S. M., Reynolds, A. B., Mehta, D., Dull, R. O., Minshall, R. D., Malik, A. B., & Liu, Y. (2015). p120-catenin expressed in alveolar type II cells is essential for the regulation of lung innate immune response.. The American journal of pathology, 185(5), 1251-63. doi:10.1016/j.ajpath.2015.01.022More infoThe integrity of the lung alveolar epithelial barrier is required for the gas exchange and is important for immune regulation. Alveolar epithelial barrier is composed of flat type I cells, which make up approximately 95% of the gas-exchange surface, and cuboidal type II cells, which secrete surfactants and modulate lung immunity. p120-catenin (p120; gene symbol CTNND1) is an important component of adherens junctions of epithelial cells; however, its function in lung alveolar epithelial barrier has not been addressed in genetic models. Here, we created an inducible type II cell-specific p120-knockout mouse (p120EKO). The mutant lungs showed chronic inflammation, and the alveolar epithelial barrier was leaky to (125)I-albumin tracer compared to wild type. The mutant lungs also demonstrated marked infiltration of inflammatory cells and activation of NF-κB. Intracellular adhesion molecule 1, Toll-like receptor 4, and macrophage inflammatory protein 2 were all up-regulated. p120EKO lungs showed increased expression of the surfactant proteins Sp-B, Sp-C, and Sp-D, and displayed severe inflammation after pneumonia caused by Pseudomonas aeruginosa compared with wild type. In p120-deficient type II cell monolayers, we observed reduced transepithelial resistance compared to control, consistent with formation of defective adherens junctions. Thus, although type II cells constitute only 5% of the alveolar surface area, p120 expressed in these cells plays a critical role in regulating the innate immunity of the entire lung.
- Chignalia, A. Z., Vogel, S. M., Reynolds, A. B., Malik, A. B., & Liu, Y. (2014). Alveolar type II cell-localized p120-catenin is an essential regulator of lung barrier function and innate immunity (660.8). The FASEB Journal, 28.More infoMaintenance of alveolar epithelial barrier (AEB) integrity is crucial for normal lung gas exchange function, fluid balance, and regulation of immune response. The mechanisms whereby AEB is kept are...
- Neves, K. B., Pestana, C. R., Queiroz, A. L., Zanotto, C. Z., Chignalia, A. Z., Valim, Y. M., Silveira, L. R., Curti, C., Tostes, R. C., & Lopes, R. A. (2014). Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement.. American journal of physiology. Heart and circulatory physiology, 306(11), H1485-94. doi:10.1152/ajpheart.00809.2013More infoTestosterone exerts both beneficial and harmful effects on the cardiovascular system. Considering that testosterone induces reactive oxygen species (ROS) generation and ROS activate cell death signaling pathways, we tested the hypothesis that testosterone induces apoptosis in vascular smooth muscle cells (VSMCs) via mitochondria-dependent ROS generation. Potential mechanisms were addressed. Cultured VSMCs were stimulated with testosterone (10(-7) mol/l) or vehicle (2-12 h) in the presence of flutamide (10(-5) mol/l), CCCP (10(-6) mol/l), mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP; 3 × 10(-5) mol/l), Z-Ile-Glu(O-ME)-Thr-Asp(O-Me) fluoromethyl ketone (Z-IETD-FMK; 10(-5) mol/l), or vehicle. ROS were determined with lucigenin and dichlorodihydrofluorescein; apoptosis, with annexin V and calcein; O2 consumption, with a Clark-type electrode, and procaspases, caspases, cytochrome c, Bax, and Bcl-2 levels by immunoblotting. Testosterone induced ROS generation (relative light units/mg protein, 2 h; 162.6 ± 16 vs. 100) and procaspase-3 activation [arbitrary units, (AU), 6 h; 166.2 ± 19 vs. 100]. CCCP, MnTMPyP, and flutamide abolished these effects. Testosterone increased annexin-V fluorescence (AU, 197.6 ± 21.5 vs. 100) and decreased calcein fluorescence (AU, 34.4 ± 6.4 vs. 100), and O2 consumption (nmol O2/min, 18.6 ± 2.0 vs. 34.4 ± 3.9). Testosterone also reduced Bax-to-Bcl-2 ratio but not cytochrome-c release from mitochondria. Moreover, testosterone (6 h) induced cleavage of procaspase 8 (AU, 161.1 ± 13.5 vs. 100) and increased gene expression of Fas ligand (2(ΔΔCt), 3.6 ± 1.2 vs. 0.7 ± 0.5), and TNF-α (1.7 ± 0.4 vs. 0.3 ± 0.1). CCCP, MnTMPyP, and flutamide abolished these effects. These data indicate that testosterone induces apoptosis in VSMCs via the extrinsic apoptotic pathway with the involvement of androgen receptor activation and mitochondria-generated ROS.
- Piegeler, T., Dull, R. O., Hu, G., Castellon, M., Chignalia, A. Z., Koshy, R. G., Votta-velis, E. G., Borgeat, A., Schwartz, D. E., Beck-schimmer, B., & Minshall, R. D. (2014). Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling.. BMC anesthesiology, 14(1), 57. doi:10.1186/1471-2253-14-57More infoAcute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a "double-hit" model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling..C57BL/6 (WT) and ICAM-1 (-/-) mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC)..WT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation ("double-hit") increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3-4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 (-/-) mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI..Ropivacaine may be a promising therapeutic agent for treating the cause of pulmonary edema by blocking inflammatory Src signaling, ICAM-1 expression, leukocyte infiltration, and vascular hyperpermeability.
- Carvalho-de-souza, J. L., Varanda, W. A., Tostes, R. C., & Chignalia, A. Z. (2013). BK Channels in Cardiovascular Diseases and Aging.. Aging and disease, 4(1), 38-49.More infoAging is a major risk factor for cardiovascular diseases, one of the main world-wide causes of death. Several structural and functional changes occur in the cardiovascular system during the aging process and the mechanisms involved in such alterations are yet to be completely described. BK channels are transmembrane proteins that play a key role in many physiological processes, including regulation of vascular tone. In vascular smooth muscle cells, BK opening and the consequent efflux of potassium (K(+)) leads to membrane hyperpolarization, which is followed by the closure of voltage-dependent Ca(2+) channels, reduction of Ca(2+) entry and vasodilatation. BK regulates nitric oxide-mediated vasodilatation and thus is crucial for normal endothelial function. Herein we will briefly review general structural properties of BK and focus on their function in the cardiovascular system emphasizing their role in cardiovascular aging and diseases.
- Ceravolo, G. S., Filgueira, F. P., Costa, T. J., Lobato, N. S., Chignalia, A. Z., Araujo, P. X., Tostes, R. C., Dantas, A. P., Fortes, Z. B., & Carvalho, M. H. (2013). Conjugated equine estrogen treatment corrected the exacerbated aorta oxidative stress in ovariectomized spontaneously hypertensive rats.. Steroids, 78(3), 341-6. doi:10.1016/j.steroids.2012.11.018More infoThe increased risk of cardiovascular diseases in postmenopausal women has been linked to the decrease in plasma estrogen levels. Preparation of conjugate equine estrogens (CEE) is one of the most routinely used hormone therapy in postmenopausal women. However, studies on the vascular effects of CEE are still sparse and the mechanism of action is not completely elucidated. In this context, we have determined the effects of CEE in the vascular oxidative stress observed in ovariectomyzed (OVX) spontaneously hypertensive rats (SHR). Mechanisms by which CEE interferes with redox-sensitive pathways and endothelial function were also determined..Aortas from OVX rats exhibited increased generation of reactive oxygen species (ROS), NADPH oxidase activity and reduced catalase protein expression, compared to aortas from sham SHR. Endothelium-intact aortic rings from OVX were hyperreactive to NE when compared to Sham aortas. This hyperreactivity was corrected by superoxide dismutase (SOD), catalase, and endothelium removal. Treatment of OVX-SHR with CEE reduced vascular ROS generation, NADPH oxidase activity, enhanced SOD and catalase expression and also corrected the NE-hyperreactivity in aortic rings from OVX-SHR..Our study indicates a potential benefit of CEE therapy through a mechanism that involves reduction in oxidative stress, improving endothelial function in OVX hypertensive rats.
- Chignalia, A. Z. (2013). Testosterone effects in the mesenteric vascular bed: ROS production, COX activation and leukocyte migration. Journal of Clinical and Experimental Cardiology. doi:10.4172/2155-9880.s1.009More infoAim: The mechanisms whereby testosterone acts in the cardiovascular system are yet to be completely described. However, oxidative stress and inflammation seem to be key players in the effects of testosterone. We sought to determine whether testosterone induces leukocyte migration and the mechanisms involved in such effect. We hypothesized that testosterone induces leukocyte migration via NADPH oxidase-driven reactive oxygen species production and cyclooxygenase-dependent mechanisms. Method and Result: Sixteen weeks-old Wistar rats were firstly treated intraperitoneally with single 5mL injections of either saline, sodium salicylate (1.25x10-3mol/L), flutamide (androgen receptor antagonist, 10-6 mol/L), apocynin (NADPH oxidase inhibitor, 3x10-4mol/L) or NS398 (COX2 inhibitor, 10-3 mol/L) and then with testosterone (10-7 mol/L). Leukocyte migration was assessed 24 hours after testosterone administration by intravital microscopy. Serum levels of testosterone were measured by ELISA. NADPH oxidase activity and subunits expression were assessed by membrane fraction-dihydroethidium fluorescence and immunoblotting, respectively. Testosterone administration did not change the serum levels of endogenous testosterone and increased venular leukocyte migration to the adventia, NADPH oxidase activity and the expression of NADPH oxidase subunits in mesenteric vessels. These effects were blocked by flutamide. Sodium salicylate partially inhibited testosterone-induced leukocyte migration. Apocynin and NS398 also inhibited testosterone-induced leukocyte migration and NADPH oxidase activity. Conclusion: Testosterone induces leukocyte migration via NADPH oxidase-dependent and COX2-related mechanisms and may contribute to inflammatory processes and oxidative stress associated with cardiovascular diseases.
- Denadai-souza, A., Lopes, L. R., Fortes, Z. B., Chignalia, A. Z., Ceravolo, G. S., Carvalho, M. H., & Camargo, L. L. (2013). PSS133 - PDI Overexpression Increases Nox1 Dependent Signaling: Effects on Vascular Dysfunction in Hypertension. Free Radical Biology and Medicine, 65, S68-S69. doi:10.1016/j.freeradbiomed.2013.10.552
- Androwiki, A. C., Denadai-souza, A., Carvalho, M. H., Lopes, L. R., Fortes, Z. B., Chignalia, A. Z., Ceravolo, G. S., & Camargo, L. L. (2012). Protein Disulfide Isomerase: A New Player in Angiotensin II Redox Signaling in Hypertension. Free Radical Biology and Medicine, 53, S156-S157. doi:10.1016/j.freeradbiomed.2012.10.427
- Chignalia, A. Z., Schuldt, E. Z., Camargo, L. L., Montezano, A. C., Callera, G. E., Laurindo, F. R., Lopes, L. R., Fortes, Z. B., Touyz, R. M., Tostes, R. C., Carvalho, M. H., & Avellar, M. C. (2012). Testosterone induces vascular smooth muscle cell migration by NADPH oxidase and c-Src-dependent pathways.. Hypertension (Dallas, Tex. : 1979), 59(6), 1263-71. doi:10.1161/hypertensionaha.111.180620More infoTestosterone has been implicated in vascular remodeling associated with hypertension. Molecular mechanisms underlying this are elusive, but oxidative stress may be important. We hypothesized that testosterone stimulates generation of reactive oxygen species (ROS) and migration of vascular smooth muscle cells (VSMCs), with enhanced effects in cells from spontaneously hypertensive rats (SHRs). The mechanisms (genomic and nongenomic) whereby testosterone induces ROS generation and the role of c-Src, a regulator of redox-sensitive migration, were determined. VSMCs from male Wistar-Kyoto rats and SHRs were stimulated with testosterone (10(-7) mol/L, 0-120 minutes). Testosterone increased ROS generation, assessed by dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence (30 minutes [SHR] and 60 minutes [both strains]). Flutamide (androgen receptor antagonist) and actinomycin D (gene transcription inhibitor) diminished ROS production (60 minutes). Testosterone increased Nox1 and Nox4 mRNA levels and p47phox protein expression, determined by real-time PCR and immunoblotting, respectively. Flutamide, actinomycin D, and cycloheximide (protein synthesis inhibitor) diminished testosterone effects on p47phox. c-Src phosphorylation was observed at 30 minutes (SHR) and 120 minutes (Wistar-Kyoto rat). Testosterone-induced ROS generation was repressed by 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine (c-Src inhibitor) in SHRs and reduced by apocynin (antioxidant/NADPH oxidase inhibitor) in both strains. Testosterone stimulated VSMCs migration, assessed by the wound healing technique, with greater effects in SHRs. Flutamide, apocynin, and 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine blocked testosterone-induced VSMCs migration in both strains. Our study demonstrates that testosterone induces VSMCs migration via NADPH oxidase-derived ROS and c-Src-dependent pathways by genomic and nongenomic mechanisms, which are differentially regulated in VSMCs from Wistar-Kyoto rats and SHRs.
- Chignalia, A. Z., Oliveira, M. A., Debbas, V., Fortes, Z. B., Touyz, R. M., Tostes, R. C., Laurindo, F. R., & Carvalho, M. H. (2010). Testosterone-induced Leukocyte Migration Involves COX2 and Redox-Sensitive Processes in rats. Free Radical Biology and Medicine, 49, S17-S18. doi:10.1016/j.freeradbiomed.2010.10.014
- Montezano, A. C., Burger, D., Paravicini, T. M., Chignalia, A. Z., Yusuf, H., Almasri, M., He, Y., Callera, G. E., He, G., Krause, K., Lambeth, D., Quinn, M. T., & Touyz, R. M. (2010). Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells.. Circulation research, 106(8), 1363-73. doi:10.1161/circresaha.109.216036More infoAlthough Nox5 (Nox2 homolog) has been identified in the vasculature, its regulation and functional significance remain unclear..We sought to test whether vasoactive agents regulate Nox5 through Ca(2+)/calmodulin-dependent processes and whether Ca(2+)-sensitive Nox5, associated with Rac-1, generates superoxide (O(2)(*-)) and activates growth and inflammatory responses via mitogen-activated protein kinases in human endothelial cells (ECs)..Cultured ECs, exposed to angiotensin II (Ang II) and endothelin (ET)-1 in the absence and presence of diltiazem (Ca(2+) channel blocker), calmidazolium (calmodulin inhibitor), and EHT1864 (Rac-1 inhibitor), were studied. Nox5 was downregulated with small interfering RNA. Ang II and ET-1 increased Nox5 expression (mRNA and protein). Effects were inhibited by actinomycin D and cycloheximide and blunted by diltiazem, calmidazolium and low extracellular Ca(2+) ([Ca(2+)](e)). Ang II and ET-1 activated NADPH oxidase, an effect blocked by low [Ca(2+)](e), but not by EHT1864. Nox5 knockdown abrogated agonist-stimulated O(2)(*-) production and inhibited phosphorylation of extracellular signal-regulated kinase (ERK)1/2, but not p38 MAPK (mitogen-activated protein kinase) or SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase). Nox5 small interfering RNA blunted Ang II-induced, but not ET-1-induced, upregulation of proliferating-cell nuclear antigen and vascular cell adhesion molecule-1, important in growth and inflammation..Human ECs possess functionally active Nox5, regulated by Ang II and ET-1 through Ca(2+)/calmodulin-dependent, Rac-1-independent mechanisms. Nox5 activation by Ang II and ET-1 induces ROS generation and ERK1/2 phosphorylation. Nox5 is involved in ERK1/2-regulated growth and inflammatory signaling by Ang II but not by ET-1. We elucidate novel mechanisms whereby vasoactive peptides regulate Nox5 in human ECs and demonstrate differential Nox5-mediated functional responses by Ang II and ET-1. Such phenomena link Ca(2+)/calmodulin to Nox5 signaling, potentially important in the regulation of endothelial function by Ang II and ET-1.
- Montezano, A. C., Zimmerman, D., Yusuf, H., Burger, D., Chignalia, A. Z., Wadhera, V., Leeuwen, F. N., & Touyz, R. M. (2010). Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium.. Hypertension (Dallas, Tex. : 1979), 56(3), 453-62. doi:10.1161/hypertensionaha.110.152058More infoArterial calcification, common in vascular diseases, involves vascular smooth muscle cell (VSMC) transformation to an osteoblast phenotype. Clinical studies suggest that magnesium may prevent this, but mechanisms are unclear. We assessed whether increasing magnesium levels reduce VSMC calcification and differentiation and questioned the role of the Mg(2+) transporter, transient receptor potential melastatin (TRPM)7 cation channels in this process. Rat VSMCs were exposed to calcification medium in the absence and presence of magnesium (2.0 to 3.0 mmol/L) or 2-aminoethoxy-diphenylborate (2-APB) (TRPM7 inhibitor). VSMCs from mice with genetically low (MgL) or high-normal (MgH) [Mg(2+)](i) were also studied. Calcification was assessed by von Kossa staining. Expression of osteocalcin, osteopontin, bone morphogenetic protein (BMP)-2, BMP-4, BMP-7, and matrix Gla protein and activity of TRPM7 (cytosol:membrane translocation) were determined by immunoblotting. Calcification medium induced osteogenic differentiation, reduced matrix Gla protein content, and increased expression of the sodium-dependent cotransporter Pit-1. Magnesium prevented calcification and decreased osteocalcin expression and BMP-2 activity and increased expression of calcification inhibitors, osteopontin and matrix Gla protein. TRPM 7 activation was decreased by calcification medium, an effect reversed by magnesium. 2-APB recapitulated the VSMC osteoblastic phenotype in VSMCs. Osteocalcin was increased by calcification medium in VSMCs and intact vessels from MgL but not MgH, whereas osteopontin was increased in MgH, but not in MgL mice. Magnesium negatively regulates vascular calcification and osteogenic differentiation through increased/restored TRPM7 activity and increased expression of anticalcification proteins, including osteopontin, BMP-7, and matrix Gla protein. New molecular insights are provided whereby magnesium could protect against VSMC calcification.
- Tirapelli, C. R., Fukada, S. Y., Yogi, A., Chignalia, A. Z., Tostes, R. C., Bonaventura, D., Lanchote, V. L., Cunha, F. Q., & Oliveira, A. M. (2008). Gender-specific vascular effects elicited by chronic ethanol consumption in rats: a role for inducible nitric oxide synthase.. British journal of pharmacology, 153(3), 468-79. doi:10.1038/sj.bjp.0707589More infoEpidemiological data suggest that the risk of ethanol-associated cardiovascular disease is greater in men than in women. This study investigates the mechanisms underlying gender-specific vascular effects elicited by chronic ethanol consumption in rats..Vascular reactivity experiments using standard muscle bath procedures were performed on isolated thoracic aortae from rats. mRNA and protein for inducible NO synthase (iNOS) and for endothelial NOS (eNOS) was assessed by RT-PCR or western blotting, respectively..In male rats, chronic ethanol consumption enhanced phenylephrine-induced contraction in both endothelium-intact and denuded aortic rings. However, in female rats, chronic ethanol consumption enhanced phenylephrine-induced contraction only in endothelium denuded aortic rings. After pre-incubation of endothelium-intact rings with L-NAME, both male and female ethanol-treated rats showed larger phenylephrine-induced contractions in aortic rings, compared to the control group. Acetylcholine-induced relaxation was not affected by ethanol consumption. The effects of ethanol on responses to phenylephrine were similar in ovariectomized (OVX) and intact (non-OVX) female rats. In the presence of aminoguanidine, but not 7-nitroindazole, the contractions to phenylephrine in rings from ethanol-treated female rats were greater than that found in control tissues in the presence of the inhibitors. mRNA levels for eNOS and iNOS were not altered by ethanol consumption. Ethanol intake reduced eNOS protein levels and increased iNOS protein levels in aorta from female rats..Gender differences in the vascular effects elicited by chronic ethanol consumption were not related to ovarian hormones but seemed to involve the upregulation of iNOS.
- Kondo, R. T., Chignalia, A. Z., Lopez, K. V., Santos, S. R., Pereira, V. A., Junior, J. O., Filho, C. R., & Carmona, M. J. (2007). Cuantificación de propofol en pequeños volúmenes de plasma usando Cromatografía Líquida deAlta Resolución con detección de fluorescencia. Latin American Journal of Pharmacy.
- Santos, L. M., Bonafe, W. W., Chignalia, A. Z., Suyama, M. J., Santos, S. R., Malbouisson, L. M., Leite, F. D., Jr, J. O., Carmona, M. J., & Auler, J. O. (2007). Influence of cardiopulmonary bypass on the plasma concentrations of atenolol.. Arquivos brasileiros de cardiologia, 88(6), 637-42. doi:10.1590/s0066-782x2007000600003More infoBetablockers are used in the treatment of angina pectoris and others ischemic coronary diseases, reducing mortality and cardiovascular events. Atenolol is a hydrophilic betablocker which is characterized by gastrointestinal absorption, small extent of distribution and renal function-dependent elimination..The study objective was to determine the inter-individual variability of atenolol in coronary patients..Plasma atenolol was quantified in six blood samples collected during the preoperative period from seven patients with coronary insufficiency and surgical indication, chronically treated with atenolol PO 25 to 100 mg/day. All patients presented a normal or slightly reduced renal function..All enrolled patients presented normal or slightly reduced renal function as a result of age and underlying disease. Atenolol plasma concentrations showed a monoexponential decline, confirming the first-order pharmacokinetics at the doses employed for the control of coronary insufficiency (mean +/- SD): 123 +/- 56, 329 +/- 96, 288 +/- 898, 258 +/- 85, 228 +/- 79 and 182 +/- 73 ng/ml at times zero, 2, 4, 6, 8 and 12h after dose administration. The investigated group showed a small inter-patient variability of atenolol administrated at multiple regimens due to the hydrophilic characteristic of the drug. Furthermore, accumulation of atenolol administered chronically was greater in coronary patients, compared to healthy subjects..In view of its cardio-selectivity and low-variability, atenolol should be used as the first-choice drug for the treatment of acute coronary syndrome and other cardiovascular diseases.
- Chignalia, A. Z., Santos, S. R., Leite, F. D., Junior, J. O., & Carmona, M. J. (2006). Disposição cinética do atenolol em pacientes coronarianos submetidos a revascularização do miocárdio. Revista Brasileira De Ciencias Farmaceuticas, 42(2), 215-221. doi:10.1590/s1516-93322006000200006More infoMyocardium ischemia is an important factor of risk for mortality and cardiovascular events in the perioperative period of cardiac and non cardiac surgeries. However, the prophylactic administration of b-blocker agents could reduce these risks. Physiologic changes, occurred during the coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB), could alter plasma concentration and pharmacokinetics of many drugs. This study investigated the pharmacokinetics of atenolol in patients with unstable angina and without renal dysfunction, submitted to CABG surgery and treated chronically with atenolol PO. For pharmacokinetic analysis, 13 blood samples were collected after doses administrated pre- and post-operatively. Compared to the pre-operative period, it was verified a non-significant reduction in the apparent volume of distribution and plasma clearance after the surgery, remaining unchanged the biological half-life, p>0.05 (NS). A negative linear correlation between plasma clearance and elimination half-life was demonstrated in both periods of the study (r: -0.77 p=0.06, pre-surgery and r: -0.89, p=0.06, post-surgery), while a correlation between volume of distribution and biological half-life was established only before revascularization (r: 0,54 p= 0,03 , pre-surgery and r: 0,09, p=0,03, post-surgery). We suggest that the CABG surgery leads to the normalization of the extension of distribution of atenolol.
- Santos, S. R., Pereira, V. A., Omosako, C. E., Chignalia, A. Z., & Carmona, M. J. (2002). Farmacocinética do atenolol no paciente coronariano cirúrgico, relato de caso. Revista Brasileira De Ciencias Farmaceuticas, 38.
- Santos, S. R., Pereira, V. A., Omosako, C. E., Chignalia, A. Z., & Carmona, M. J. (2002). mobilização do propranolol pelo estresse cirúrgico em pacientes submetidos a cirurgia cardíaca com circulação extracorpórea: estudo de dois casos. Revista Brasileira De Ciencias Farmaceuticas, 38.
Proceedings Publications
- Chignalia, A. Z. (2022). Abstract 15352: Lung Endothelial Transport in Glypican 1 Knockout Mice. In Circulation - AHA Scientific Sessions, 146:A15352.More infoScientific Sessions - American Heart Association
- Chignalia, A., & Thota, L. (2022). Abstract P3012: Syndecan 1 Regulates Lung Endothelial Barrier Function In Homeostatic And Injury Conditions. In Circulation Research, 131.
- Thota, L. R., De Souza, J. L., & Chignalia, A. Z. (2022, Fall). Novel mechanisms underlying heart failure induced by pressure overload. In Free Radical Biology and Medicine, 192, 56-57.
- Souza, D., Chignalia, A. Z., & Carvalho-de-souza, J. L. (2021). Modulation of Ventricular Cardiomyocytes Electrophysiology by Glypican 1 Heparan Sulfate Proteoglycan. In Biophysical Journal, 120, 244a.
Presentations
- Chignalia, A. Z. (2023). Glypican 1: a potentail target to treat heart failure. UA College of Medicine Research Day.
- Chignalia, A. Z., De Souza, J. L., Zemskov, E., & Black, S. (2021). RhoA Mediates Pressure-Induced Endothelial Hyperpermeability. AHA Scientific Session. Virtual: AHA.More infoCirculation 144 (Suppl_1), A13551-A13551
- Chignalia, A. Z., & Black, S. (2020, April/Spring). Glypican‐1 Is a Trigger for Pulmonary Edema Development During Acute Heart Failure. Experimental Biology.
- Potje, S., Katiki, A., Isbatan, A., Bendhack, L., Dull, R., & Chignalia, A. Z. (2019, February). The endothelial glycocalyx as a regulator of vascular tone. XXIII Brazilian Symposium of Cardiovascular Physiology.
Poster Presentations
- Chignalia, A. Z., De Souza, J. L., & Rosales, J. L. (2023, October/Fall).
Glypican 1 and intracellular calcium levels in lung endothelial cells
. ASIP 2023 Joint Meeting of ASMB, HCS, and ASIP. Salt Lake City. - Chignalia, A. Z., De Souza, J. L., Bendhack, L., Potje, S., & Thota, L. (2023, July/Summer). New Insights Into The Role Of The Glycocalyx Components In Heart Failure Induced By Pressure Overload. Basic Cardiovascular Sciences (BCVS). Boston.
- Chignalia, A. Z., Potje, S., Bendhack, L., De Souza, J. L., & Thota, L. (2023). New Insights Into The Role Of The Glycocalyx Components In Heart Failure Induced By Pressure Overload.. Basic Cardiovascular Sciences, American Heart Association. Boston, USA.
- Rosalez, J. L., De Souza, J. L., & Chignalia, A. Z. (2023). Glypican 1 and intracellular calcium levels in lung endothelial cells. ASIP 2023 Joint Meeting of ASMB, HCS, and ASIP.
- Black, S. M., Zemskov, E., De Souza, J. L., & Chignalia, A. Z. (2021, Nov / Fall). RhoA Mediates Pressure-Induced Endothelial Hyperpermeability. CirculationLippincott Williams & Wilkins.
- Black, S., Zemskov, E., De Souza, J. L., & Chignalia, A. Z. (2022). Lung endothelial transport in glypican 1 knockout mice. Scientific Sessions American heart Association.
- De Souza, J. L., Chignalia, A. Z., & Souza, D. (2021, February/Winter). Modulation of ventricular cardiomyocytes electrophysiology by glypican 1 heparan sulfate proteoglycan.. 65th Biophysical Society Annual Meeting. on line: Biophysical Society.
- Thota, L. R., De Souza, J. L., & Chignalia, A. Z. (2022, November). Novel mechanisms underlying heart failure by pressure overload. SfRBM 29th Annual Conference. Orlando: SfRBM.
- Thota, L., & Chignalia, A. Z. (2022). Syndecan 1 Regulates Lung Endothelial Barrier Function In Homeostatic And Injury Conditions. BCVS American Heart Association.
- Chignalia, A. Z., & De Souza, J. L. (2021, February/Winter). MODULATION OF VENTRICULAR CARDIOMYOCYTES ELECTROPHYSIOLOGY BY GLYPICAN 1 HEPARAN SULFATE PROTEOGLYCAN.. Biophysical Society 65th Annual Meeting.
- Chignalia, A. Z., De Souza, J. L., & Dull, R. (2020, April/Spring). Glypican‐1 and Remodeling Cardiac Hypertrophy.. Experimental Biology.
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