Olga Rafikova

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Journals/Publications

• Gillis, E. E., Brinson, K. N., Rafikova, O., Chen, W., Musall, J. B., Harrison, D. G., & Sullivan, J. C. (2018). Oxidative stress induces BH deficiency in male, but not female, SHR. Bioscience reports, 38(4).
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  We previously published that female spontaneously hypertensive rats (SHR) have significantly greater nitric oxide (NO) bioavailability and NO synthase (NOS) enzymatic activity in the renal inner medulla (IM) compared with age-matched males, although the mechanism responsible remains unknown. Tetrahydrobiopterin (BH) is a critical cofactor required for NO generation, and decreases in BH as a result of increases in oxidative stress have been implicated in the pathogenesis of hypertension. As male SHR are known to have higher levels of oxidative stress compared with female SHR, we hypothesized that relative BH deficiency induced by oxidative stress in male SHR results in lower levels of NOS activity in renal IM compared with females. Twelve-week-old male and female SHR were randomized to receive tempol (30 mg/kg/day via drinking water) or vehicle for 2 weeks. Tempol treatment did not affect blood pressure (BP) in either sex, but reduced peroxynitrite levels only in males. Females had more total biopterin, dihydrobiopterin (BH), and BH levels in renal IMs than males, and tempol treatment eliminated these sex differences. Females had greater total NOS activity in the renal IM than males, and adding exogenous BH to the assay increased NOS activity in both sexes. This sex difference in total NOS and the effect of exogenous BH were abolished with tempol treatment. We conclude that higher oxidative stress in male SHR results in a relative deficiency of BH compared with females, resulting in diminished renal NOS activity in the male.
• Kurdyukov, S., Eccles, C. A., Desai, A. A., Gonzalez-Garay, M., Yuan, J. X., Garcia, J. G., Rafikova, O., & Rafikov, R. (2018). New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension. PloS one, 13(8), e0203493.
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  Pulmonary Arterial Hypertension (PAH) is a fatal disorder with limited treatment options and reduced life expectancy after diagnosis. Complex genetic backgrounds in PAH complicates identification of causative mutations that is essential for an understanding of the disease diagnostics and etiology especially for idiopathic PAH (iPAH). Hemolysis has been implicated as contributing to the pathobiology of PAH. Glucose-6-Phosphate Dehydrogenase (G6PD) expression and activity define erythrocyte's antioxidant capacity, and its decrease contributes to erythrocyte fragility. As G6PD deficiency was previously reported in a limited number of PAH cases, we tested whether iPAH patients exhibit underlying G6PD alterations in erythrocytes. A cohort of 22 PAH patients and 8 non-PAH patients were recruited for this study. DNA isolated from Peripheral Blood Mononuclear Cells (PBMC) was used for detection of mutations in the coding region of the G6PD gene. RNA isolated from PBMC was used for determination of G6PD mRNA expression level. G6PD activity was measured in Red Blood Cell (RBC) pellets. Three patients had missense mutations in G6PD (Val291Met, Asn126Asp, Asp194Glu), however, only one mutation (Val291Met) results in a severe G6PD deficiency. A single patient with mutation (Asn126Asp) showed a 21% decrease in G6PD activity, two subjects showed G6PD deficiency without mutations, and one patient had a decreased level of G6PD mRNA and reduced enzyme levels. This study demonstrates that a moderate decrease in G6PD activity is associated with PAH. Screening for G6PD activity and mutations in the G6PD gene may provide early detection of individuals predisposed to PAH.
• Rafikov, R., McBride, M. L., Zemskova, M., Kurdyukov, S., McClain, N., Niihori, M., Langlais, P. R., & Rafikova, O. (2018). INOSITOL MONOPHOSPHATASE 1 (IMPA1) AS A NOVEL INTERACTING PARTNER OF RAGE IN PULMONARY HYPERTENSION. American journal of physiology. Lung cellular and molecular physiology.
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  Pulmonary arterial hypertension (PAH) is a lethal disease characterized by progressive pulmonary vascular remodeling. The receptor for advanced glycation endproducts (RAGE) plays an important role in PAH by promoting proliferation of pulmonary vascular cells. RAGE is also known to mediate activation of Akt signaling, although the particular molecular mechanism remains unknown. This study aimed to identify the interacting partner of RAGE that could facilitate RAGE-mediated Akt activation and vascular remodeling in PAH. The progressive angioproliferative PAH was induced in 24 female Sprague-Dawley rats (n=8/group) that were randomly assigned to develop PAH for one, two or five weeks (right ventricle peak systolic pressure (RVPSP) 56.5±3.2mmHg, 63.6±1.6mmHg and 111.1±4.5mmHg respectively vs. 22.9±1.1mmHg in Controls). PAH triggered early and late episodes of apoptosis in rat lungs accompanied by RAGE activation. Mass spectrometry analysis has identified IMPA1 as a novel PAH-specific interacting partner of RAGE. The proximity ligation assay (PLA) confirmed the formation of RAGE/IMPA1 complex in the pulmonary artery wall. Activation of IMPA1 in response to increased glucose-6-phosphate (G6P) is known to play a critical role in inositol synthesis and recycling. Indeed, we confirmed a 3-fold increase of G6P (p=0.0005) levels in lungs of PAH rats starting from week 1 that correlated with accumulation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), membrane translocation of PI3K, and a 3-fold increase in membrane Akt levels (p=0.02) and Akt phosphorylation. We conclude that the formation of the newly discovered RAGE/IMPA1 complex could be responsible for the stimulation of inositol pathways and activation of Akt signaling in PAH.
• Rafikova, O., Srivastava, A., Desai, A. A., Rafikov, R., & Tofovic, S. P. (2018). Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung. Respiratory research, 19(1), 69.
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  Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents.
• Rafikova, O., Williams, E. R., McBride, M. L., Zemskova, M., Srivastava, A., Nair, V., Desai, A. A., Langlais, P. R., Zemskov, E., Simon, M., Mandarino, L. J., & Rafikov, R. (2018). Hemolysis-induced Lung Vascular Leakage Contributes to the Development of Pulmonary Hypertension. American journal of respiratory cell and molecular biology, 59(3), 334-345.
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  Although hemolytic anemia-associated pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are more common than the prevalence of idiopathic PAH alone, the role of hemolysis in the development of PAH is poorly characterized. We hypothesized that hemolysis independently contributes to PAH pathogenesis via endothelial barrier dysfunction with resulting perivascular edema and inflammation. Plasma samples from patients with and without PAH (both confirmed by right heart catheterization) were used to measure free hemoglobin (Hb) and its correlation with PAH severity. A sugen (50 mg/kg)/hypoxia (3 wk)/normoxia (2 wk) rat model was used to elucidate the role of free Hb/heme pathways in PAH. Human lung microvascular endothelial cells were used to study heme-mediated endothelial barrier effects. Our data indicate that patients with PAH have increased levels of free Hb in plasma that correlate with PAH severity. There is also a significant accumulation of free Hb and depletion of haptoglobin in the rat model. In rats, perivascular edema was observed at early time points concomitant with increased infiltration of inflammatory cells. Heme-induced endothelial permeability in human lung microvascular endothelial cells involved activation of the p38/HSP27 pathway. Indeed, the rat model also exhibited increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling, there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF-1a during the first 2 weeks of PH regardless of hypoxic conditions. Our data suggest that hemolysis may play a significant role in PAH pathobiology.
• Rafikov, R., & Rafikova, O. (2017). Pulmonary arterial hypertension: are we close to the success?. Journal of Clinical Respiratory Medicine, 1(1), 1-3.
• Sakipov, S., Rafikova, O., Kurnikova, M. G., & Rafikov, R. (2017). Molecular mechanisms of bio-catalysis of heme extraction from hemoglobin. Redox biology, 11, 516-523.
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  Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. We propose an approach that helps to eliminate extracellular hemoglobin toxicity in SCD by employing a bacterial protein system that evolved to extract heme from extracellular hemoglobin. NEAr heme Transporter (NEAT) domains from iron-regulated surface determinant proteins from Staphylococcus aureus specifically bind free heme as well as facilitate its extraction from hemoglobin. We demonstrate that a purified NEAT domain fused with human haptoglobin β-chain is able to remove heme from hemoglobin and reduce heme content and peroxidase activity of hemoglobin. We further use molecular dynamics (MD) simulations to resolve molecular pathway of heme transfer from hemoglobin to NEAT, and to elucidate molecular mechanism of such heme transferring process. Our study is the first of its kind, in which simulations are employed to characterize the process of heme leaving hemoglobin and subsequent rebinding with a NEAT domain. Our MD results highlight important amino acid residues that facilitate heme transfer and will guide further studies for the selection of best NEAT candidate to attenuate free hemoglobin toxicity.
• Chen, F., Wang, Y., Rafikov, R., Haigh, S., Zhi, W. B., Kumar, S., Doulias, P. T., Rafikova, O., Pillich, H., Chakraborty, T., Lucas, R., Verin, A. D., Catravas, J. D., She, J. X., Black, S. M., & Fulton, D. J. (2016). RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G(+)-bacterial toxins. Biochemical pharmacology.
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  Disruption of the endothelial barrier in response to Gram positive (G(+)) bacterial toxins is a major complication of acute lung injury (ALI) and can be further aggravated by antibiotics which stimulate toxin release. The integrity of the pulmonary endothelial barrier is mediated by the balance of disruptive forces such as the small GTPase RhoA, and protective forces including endothelium-derived nitric oxide (NO). How NO protects against the barrier dysfunction is incompletely understood and our goal was to determine whether NO and S-nitrosylation can modulate RhoA activity and whether this mechanism is important for G(+) toxin-induced microvascular permeability. We found that the G(+) toxin listeriolysin-O (LLO) increased RhoA activity and that NO and S-NO donors inhibit RhoA activity. RhoA was robustly S-nitrosylated as determined by biotin-switch and mercury column analysis. MS revealed that three primary cysteine residues are S-nitrosylated including cys16, cys20 and cys159. Mutation of these residues to serine diminished S-nitrosylation to endogenous NO and mutant RhoA was less sensitive to inhibition by S-NO. G(+)-toxins stimulated the denitrosylation of RhoA which was not mediated by S-nitrosoglutathione reductase (GSNOR), thioredoxin (TRX) or thiol-dependent enzyme activity but was instead stimulated directly by elevated calcium levels. Calcium-promoted the direct denitrosylation of WT but not mutant RhoA and mutant RhoA adenovirus was more effective than WT in disrupting the barrier integrity of human lung microvascular endothelial cells. In conclusion, we reveal a novel mechanism by which NO and S-nitrosylation reduces RhoA activity which may be of significance in the management of pulmonary endothelial permeability induced by G(+)-toxins.
• Rafikova, O., Meadows, M. L., Kinchen, J. M., Mohney, R. P., Maltepe, E., Desai, A. A., Yuan, J. X., Garcia, J. G., Fineman, J. R., Rafikov, R., & Black, S. M. (2016). Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung. PloS one, 11(3), e0150480.
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  There is increasing interest in the potential for metabolic profiling to evaluate the progression of pulmonary hypertension (PH). However, a detailed analysis of the metabolic changes in lungs at the early stage of PH, characterized by increased pulmonary artery pressure but prior to the development of right ventricle hypertrophy and failure, is lacking in a preclinical animal model of PH. Thus, we undertook a study using rats 14 days after exposure to monocrotaline (MCT), to determine whether we could identify early stage metabolic changes prior to the manifestation of developed PH. We observed changes in multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis. Further, our global metabolic profile data compare favorably with prior work carried out in humans with PH. We conclude that despite the MCT-model not recapitulating all the structural changes associated with humans with advanced PH, including endothelial cell proliferation and the formation of plexiform lesions, it is very similar at a metabolic level. Thus, we suggest that despite its limitations it can still serve as a useful preclinical model for the study of PH.
• Rafikova, O., Rafikov, R., Kangath, A., Qu, N., Aggarwal, S., Sharma, S., Desai, J., Fields, T., Ludewig, B., Yuan, J. X., Jonigk, D., & Black, S. M. (2016). Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension. Free radical biology & medicine, 95, 96-111.
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  The development of pulmonary hypertension (PH) involves the uncontrolled proliferation of pulmonary smooth muscle cells via increased growth factor receptor signaling. However, the role of epidermal growth factor receptor (EGFR) signaling is controversial, as humans with advanced PH exhibit no changes in EGFR protein levels and purpose of the present study was to determine whether there are post-translational mechanisms that enhance EGFR signaling in PH. The EGFR inhibitor, gefinitib, significantly attenuated EGFR signaling and prevented the development of PH in monocrotaline (MCT)-exposed rats, confirming the contribution of EGFR activation in MCT induced PH. There was an early MCT-mediated increase in hydrogen peroxide, which correlated with the binding of the active metabolite of MCT, monocrotaline pyrrole, to catalase Cys377, disrupting its multimeric structure. This early oxidative stress was responsible for the oxidation of EGFR and the formation of sodium dodecyl sulfate (SDS) stable EGFR dimers through dityrosine cross-linking. These cross-linked dimers exhibited increased EGFR autophosphorylation and signaling. The activation of EGFR signaling did not correlate with pp60(src) dependent Y845 phosphorylation or EGFR ligand expression. Importantly, the analysis of patients with advanced PH revealed the same enhancement of EGFR autophosphorylation and covalent dimer formation in pulmonary arteries, while total EGFR protein levels were unchanged. As in the MCT exposed rat model, the activation of EGFR in human samples was independent of pp60(src) phosphorylation site and ligand expression. This study provides a novel molecular mechanism of oxidative stress stimulated covalent EGFR dimerization via tyrosine dimerization that contributes into development of PH.
• Rafikov, R., Sun, X., Rafikova, O., Meadows, M. L., Desai, A. A., Khalpey, Z., Yuan, J. X., Fineman, J. R., & Black, S. M. (2015). Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells. Redox biology, 6, 278-86.
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  ATP is essential for cellular function and is usually produced through oxidative phosphorylation. However, mitochondrial dysfunction is now being recognized as an important contributing factor in the development cardiovascular diseases, such as pulmonary hypertension (PH). In PH there is a metabolic change from oxidative phosphorylation to mainly glycolysis for energy production. However, the mechanisms underlying this glycolytic switch are only poorly understood. In particular the role of the respiratory Complexes in the mitochondrial dysfunction associated with PH is unresolved and was the focus of our investigations. We report that smooth muscle cells isolated from the pulmonary vessels of rats with PH (PH-PASMC), induced by a single injection of monocrotaline, have attenuated mitochondrial function and enhanced glycolysis. Further, utilizing a novel live cell assay, we were able to demonstrate that the mitochondrial dysfunction in PH-PASMC correlates with deficiencies in the activities of Complexes I-III. Further, we observed that there was an increase in mitochondrial reactive oxygen species generation and mitochondrial membrane potential in the PASMC isolated from rats with PH. We further found that the defect in Complex I activity was due to a loss of Complex I assembly, although the assembly of Complexes II and III were both maintained. Thus, we conclude that loss of Complex I assembly may be involved in the switch of energy metabolism in smooth muscle cells to glycolysis and that maintaining Complex I activity may be a potential therapeutic target for the treatment of PH.
• Rafikova, O., Rafikov, R., Meadows, M. L., Kangath, A., Jonigk, D., & Black, S. M. (2015). The sexual dimorphism associated with pulmonary hypertension corresponds to a fibrotic phenotype. Pulmonary circulation, 5(1), 184-97.
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  Although female predominance in the development of all types of pulmonary hypertension (PH) is well established, many clinical studies have confirmed that females have better prognosis and higher survival rate than males. There is no clear explanation of why sex influences the pathogenesis and progression of PH. Using a rat angioproliferative model of PH, which closely resembles the primary pathological changes observed in humans, we evaluated the role of sex in the development and progression of PH. Female rats had a more pronounced increase in medial thickness in the small pulmonary arteries. However, the infiltration of small pulmonary arteries by inflammatory cells was found only in male rats, and this corresponded to increased myeloperoxidase activity and abundant adventitial and medial fibrosis that were not present in female rats. Although the level of right ventricle (RV) peak systolic pressure was similar in both groups, the survival rate in male rats was significantly lower. Moreover, male rats presented with a more pronounced increase in RV thickness that correlated with diffuse RV fibrosis and significantly impaired right cardiac function. The reduction in fibrosis in female rats correlated with increased expression of caveolin-1 and reduced endothelial nitric oxide synthase-derived superoxide. We conclude that, in the pathogenesis of PH, female sex is associated with greater remodeling of the pulmonary arteries but greater survival. Conversely, in males, the development of pulmonary and cardiac fibrosis leads to early and severe RV failure, and this may be an important reason for the lower survival rate among males.

Presentations

• Rafikov, R., Rafikova, O., Niihori, M., Zemskova, M., Eccles, C., & Kurdyukov, S. (2018, Nov). Pulmonary hypertension in rats with human mutation of NFU1 is oxygen sensitive. Society for redox biology and medicine. Chicago, IL.
• Rafikova, O. (2015, November). Reductive stress associated with male gender contributes to the pulmonary hypertension and right ventricle dysfunction.. SFRBM meeting, Boston MA.

Poster Presentations

• McBride, M. L., Langlais, P. R., Rafikov, R., & Rafikova, O. (2018, May). Receptor for Advanced Glycation Endproducts (RAGE) regulates metabolic reprogramming induced over-proliferation in pulmonary hypertension. American Thoracic Society.
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  Our data indicate that PH patients have increased levels of free Hb in plasma that correlate with disease severity and progression. There is also a significant accumulation of free Hb and depletion of haptoglobin in the sugen/hypoxia rat model. In rats, perivascular edema was observed during first two weeks of PH concomitant with increased infiltration of inflammatory cells. In the cell culture model of HLMVECs, we found that not hemoglobin but free heme-induced endothelial permeability via activation of the p38/HSP27 signaling pathway. Indeed, the rat model also exhibited an increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling; there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF1a during the first two weeks of PAH regardless of hypoxic conditions. We found that heme-mediated effects on endothelium, at least in part, depend on Heme Carrier Protein 1 (HCP-1) and pharmacological inhibition of HCP-1 by sulfasalazine reduced barrier disruptive potential of the heme. Sulfasalazine administration to sugen/hypoxia rats results in attenuation of PH by a reduction in vascular remodeling in the lungs as well as decreasing right heart hypertrophy.
• Rafikov, R., Rafikova, O., Langlais, P. R., Vasylev, M., Eccles, C., & Tofovic, S. (2018, Nov). Inhibition of respiratory chain Complex III irreversibly changes the mitochondria proteomic landscape. Society for redox biology and medicine. Chicago, IL.
• Rafikov, R., Srivastava, A., Desai, A., Langlais, P. R., Zemskov, E., Mandarino, L. J., & Rafikova, O. (2018, May). Free heme-mediated endothelial barrier dysfunction contributes to the development of pulmonary hypertension. American Thoracic Society.
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  Our data indicate that PH patients have increased levels of free Hb in plasma that correlate with disease severity and progression. There is also a significant accumulation of free Hb and depletion of haptoglobin in the sugen/hypoxia rat model. In rats, perivascular edema was observed during first two weeks of PH concomitant with increased infiltration of inflammatory cells. In the cell culture model of HLMVECs, we found that not hemoglobin but free heme-induced endothelial permeability via activation of the p38/HSP27 signaling pathway. Indeed, the rat model also exhibited an increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling; there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF1a during the first two weeks of PAH regardless of hypoxic conditions. We found that heme-mediated effects on endothelium, at least in part, depend on Heme Carrier Protein 1 (HCP-1) and pharmacological inhibition of HCP-1 by sulfasalazine reduced barrier disruptive potential of the heme. Sulfasalazine administration to sugen/hypoxia rats results in attenuation of PH by a reduction in vascular remodeling in the lungs as well as decreasing right heart hypertrophy.
• Rafikova, O., Rafikov, R., & Desai, A. (2018, July). Male gender predisposes PAH patients to reductive stress and disease progression. Pulmonary Hypertension Association's 2018 International PH Conference and Scientific Sessions.
• Rafikova, O., Rafikov, R., Niihori, M., & Eccles, C. (2018, November). Rats with Human Mutation of Fe-S Cluster Scaffold Protein NFU1 Develop Pulmonary Hypertension. American Heart Association - Scientific Sessions.
• Rafikova, O., Rafikov, R., Zemskov, M., & Kurdyukov, S. (2018, July). Gender difference on the cellular level: distinct stress responses in male and female endothelial cells isolated from mouse lungs. Pulmonary Hypertension Association's 2018 International PH Conference and Scientific Sessions.
• Rafikova, O., Rafikov, R., Zemskova, M., & Sergey Kurdyukov, S. (2018, November). Isolated Pulmonary Endothelial Cells Preserve Gender Specific Sensitivity to Stress. American Heart Association - Scientific Sessions.
• Vasilyev, M., Langlais, P. R., Rafikova, O., & Rafikov, R. (2018, Novermber/Fall). Inhibition of respiratory chain Complex III irreversibly changes mitochondria proteomic landscape. The Society for Redox Biology and Medicine's 25th Annual Conference.
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  The role of mitochondria dysfunction in the pathogenesis of pulmonary hypertension (PH) is currently well-recognized. However, the particular mechanisms and the type of mitochondrial dysfunction are still being debated. We have recently shown that chronic inhibition of oxidative phosphorylation by Antimycin A (AA) results in increased pulmonary pressure and remodeled pulmonary arteries. AA (0.35mg/kg) was given to rats three times for six days and lungs were analyzed 30 minutes (acute effect), 12 and 24 days (chronic effect) after the first AA injection. Mitochondria isolated from lungs were subjected to mass spectrometry and quantitative proteomic analysis to estimate changes in the isolated mitochondrial proteome over the course of disease development. Using a 4-fold change cutoff value for effects on protein expression, 48 mitochondrial proteins were discovered to be altered upon AA treatment, with 13 proteins exhibiting a significant difference (ANOVA). Our data indicate that using a 4-fold cutoff w distinguished between the control and 24 day groups by principal component analysis (PCA). Functional analysis of the proteome data revealed major downregulation of enzymes involved in fatty acids oxidation (ACDSB, HADH) and fatty acids transport (CPT1, ACSM5). Electron transport chain proteins showed mixed results with downregulation of Complex IV (COX1/2), altered Complex I subunits (NU4/5M) and assembly protein expression (NDUF4), and upregulation of ubiquinone biosynthesis (COQ3/7). Activation of ubiquinone biosynthesis could be explained as compensation for inhibition of mitochondrial respiration by AA. Mitochondrial machinery for importing proteins into the matrix (TIM9/10/13) was upregulated, but peptidases (LON, MPPA) that control the quality of matrix proteins were downregulated. Finally, proteins that regulate mitochondria morphology (MIRO2, PGAM5, TMM11) and degradation pathways (MIEAP, BCL2) were altered. Collectively, our data indicate that chronic inhibition of the respiratory chain for six days leads to irreversible changes in the proteomic landscape of mitochondria. These changes reprogram mitochondria to a different metabolic state and altered morphology that have been found in various models of PH and PH patients.
• McBride, M. L., Williams, E. R., Langlais, P. R., Mandarino, L. J., Rafikov, R., & Rafikova, O. (2017, June). Inositol Monophosphate 1 (IMPA1) And Rage Interaction: The Role Of Novel Proliferative Pathway In Pulmonary Hypertension. American Heart Association.
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  This is a very first evidence that damage induced RAGE activation is involved in protection from glycolysis-mediated osmotic stress and activation of Akt pathway in PAH by the formation of RAGE/IMPA1 complex.
• Rafikov, R., Srivastava, A., Desai, A., Langlais, P. R., Zemskov, E., Mandarino, L. J., & Rafikova, O. (2017, June). Hemolysis-mediated vascular permeability in lungs contributes to the development of pulmonary hypertension. American Heart Association.
  More info

  Our data indicate that PH patients have increased levels of free Hb in plasma that correlate with disease severity and progression. There is also a significant accumulation of free Hb and depletion of haptoglobin in the sugen/hypoxia rat model. In rats, perivascular edema was observed during first two weeks of PH concomitant with increased infiltration of inflammatory cells. In the cell culture model of HLMVECs, we found that not hemoglobin but free heme-induced endothelial permeability via activation of the p38/HSP27 signaling pathway. Indeed, the rat model also exhibited an increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling; there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF1a during the first two weeks of PAH regardless of hypoxic conditions. We found that heme-mediated effects on endothelium, at least in part, depend on Heme Carrier Protein 1 (HCP-1) and pharmacological inhibition of HCP-1 by sulfasalazine reduced barrier disruptive potential of the heme. Sulfasalazine administration to sugen/hypoxia rats results in attenuation of PH by a reduction in vascular remodeling in the lungs as well as decreasing right heart hypertrophy.
• Rafikova, O. (2015, July). Akt Mediated Mitochondrial Dysfunction Involves Mitochondrial Endothelial Nitric Oxide Synthase Translocation. AHA BCVS meeting, New Orleans, LA..
• Rafikova, O. (2015, July). Pulmonary Hypertension Induced Right Ventricle Fibrosis is Associated with Male Gender. AHA BCVS meeting, New Orleans, LA.
• Rafikova, O. (2015, November). Complex I dysfunction dictates glycolytic switch in pulmonary hypertensive smooth muscle cells.. SFRBM meeting, Boston MA.
• Rafikova, O. (2015, November). Metabolic changes precede the development of pulmonary hypertension in monocrotaline model.. SFRBM meeting, Boston MA.
• Rafikova, O. (2015, November). Targeted protein protection from oxidative/nitrosative post-translational modifications using shielding peptides.. SFRBM meeting, Boston MA.