- Research Assistant Professor, Medicine
- Young Author Achievement Awards
- American College of Cardiology, Spring 2019
- CSCTR ANNUAL MEETING TRAVeL AWARD
- Central Society for Clinical and Translational Research, Summer 2016
- American Federation for Medical Research Midwestern Region Scholar Award
- American Federation for Medical Research, Spring 2015
- CSCTR ANNUAL MEETING ORAL ABSTRACT AWARD
- Central Society for Clinical and Translational Research, Spring 2015
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- Huang, J., Lu, W., Ouyang, H., Chen, Y., Zhang, C., Luo, X., Li, M., Shu, J., Zheng, Q., Chen, H., Chen, J., Tang, H., Sun, D., Yuan, J. X., Yang, K., & Wang, J. (2020). Transplantation of Mesenchymal Stem Cells Attenuates Pulmonary Hypertension by Normalizing the Endothelial-to-Mesenchymal Transition. American journal of respiratory cell and molecular biology, 62(1), 49-60.More infoFor decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For experiments, the transplanted GFP MSCs were traced at different time points in the lung tissue of a chronic hypoxia-induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia-induced PH models. For experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia-induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2α, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.
- Karnes, J. H., Wiener, H. W., Schwantes-An, T. H., Natarajan, B., Sweatt, A. J., Chaturvedi, A., Arora, A., Batai, K., Nair, V., Steiner, H. E., Giles, J. B., Yu, J., Hosseini, M., Pauciulo, M. W., Lutz, K. A., Coleman, A. W., Feldman, J., Vanderpool, R., Tang, H., , Garcia, J. G., et al. (2020). Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine.More infoLimited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).
- Tang, H., Vanderpool, R. R., Wang, J., & Yuan, J. X. (2020). Targeting L-arginine-nitric oxide-cGMP pathway in pulmonary arterial hypertension. Pulmonary circulation, 7(3), 569-571.
- Zhu, Z., Godana, D., Li, A., Rodriguez, B., Gu, C., Tang, H., Minshall, R. D., Huang, W., & Chen, J. (2020). Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension. Pulmonary circulation, 9(2), 2045894019841987.More infoEchocardiography, a non-invasive and cost-effective method for monitoring cardiac function, is commonly used for evaluation and pre-clinical diagnostics of pulmonary hypertension (PH). Previous echocardiographic studies in experimental models of PH are fragmentary in terms of the evaluation of right ventricle (RV) function. In this study, three rodent models of PH: a mouse model of hypoxia-induced PH, a rat model of hypoxia+Sugen induced PH and a rat model of monocrotaline-induced PH, were employed to measure RV fractional area change (RVFAC), RV free wall thickness (RVFWT), pulmonary acceleration time (PAT), pulmonary ejection time (PET), and tricuspid annular plane systolic excursion (TAPSE). We found that, in these models, RVFWT significantly increased, but RVFAC, PAT, or PAT/PET ratios and TAPSE values significantly decreased. Accurate and complete TAPSE patterns were demonstrated in the three rodent models of PH. The RV echocardiography data matched the corresponding invasive hemodynamic and heart histologic data in each model. This serves as a reference study for real-time and non-invasive evaluation of RV function in rodent models of PH using echocardiography.
- Rhodes, C. J., Batai, K., Bleda, M., Haimel, M., Southgate, L., Germain, M., Pauciulo, M. W., Hadinnapola, C., Aman, J., Girerd, B., Arora, A., Knight, J., Hanscombe, K. B., Karnes, J. H., Kaakinen, M., Gall, H., Ulrich, A., Harbaum, L., Cebola, I., , Ferrer, J., et al. (2019). Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. The Lancet. Respiratory medicine, 7(3), 227-238.More infoRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
- Sun, H., Zhang, F., Xu, Y., Sun, S., Wang, H., Du, Q., Gu, C., Black, S. M., Han, Y., & Tang, H. (2019). Salusin-β Promotes Vascular Calcification Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation. Antioxidants & redox signaling, 31(18), 1352-1370.More infoVascular calcification (VC) is a hallmark feature of cardiovascular disease and a significant risk factor for morbidity and mortality. Salusin-β exerts cardiovascular regulating effects in hypertension, atherosclerosis, and diabetes. The present study was designed to examine the roles of salusin-β in the progression of VC and its downstream signaling mechanisms. Salusin-β expression in both the aortas of VC rats induced by vitamin D3 and nicotine and vascular smooth muscle cells (VSMCs) incubated with calcifying media was increased. Salusin-β knockdown remarkably reduced VC, whereas overexpression of salusin-β exacerbated VC both and . Overexpression of salusin-β promoted the VSMC osteochondrogenic transition, decreased Klotho protein levels, enhanced Ras-related C3 botulinum toxin substrate 1 (Rac1) activity and the translocation of p47phox to the membrane, increased the expression of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits and the production of reactive oxygen species (ROS) with or without calcifying media; however, salusin-β deficiency played the opposite roles. The calcification and downregulated Klotho protein levels induced by salusin-β were restored by ROS scavenger N-acetyl-l-cysteine, diphenyleneiodonium chloride [an inhibitor of flavin-containing enzyme, including NAD(P)H oxidase], or gene knockdown of NAD(P)H oxidase (NOX)-2, p22phox, or p47phox but were not affected by NOX-1 and NOX-4 knockdown. Klotho knockdown attenuated the protective effect of salusin-β deficiency on VSMC calcification. By contrast, exogenous Klotho ameliorated the development of VC and ROS generation induced by salusin-β overexpression. Salusin-β is a critical modulator in VC. Salusin-β regulates VC through activation of NAD(P)H/ROS-mediated Klotho downregulation, suggesting that salusin-β may be a novel target for treatment of VC.
- Wang, Z., Yang, K., Zheng, Q., Zhang, C., Tang, H., Babicheva, A., Jiang, Q., Li, M., Chen, Y., Carr, S. G., Wu, K., Zhang, Q., Balistrieri, A., Wang, C., Song, S., Ayon, R. J., Desai, A. A., Black, S. M., Garcia, J. G., , Makino, A., et al. (2019). Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology, 316(1), L216-L228.More infoThe tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca entry to increase cytosolic Ca concentration ([Ca]). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca entry (SOCE) induced by passive depletion of intracellularly stored Ca in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.
- Dai, J., Zhou, Q., Tang, H., Chen, T., Li, J., Raychaudhuri, P., Yuan, J. X., & Zhou, G. (2018). Smooth muscle cell-specific FoxM1 controls hypoxia-induced pulmonary hypertension. Cellular signalling, 51, 119-129.More infoForkhead box M1 (FoxM1) is a transcription factor that promotes cell proliferation by regulating a broad spectrum of genes that participate in cell cycle regulation, such as Cyclin B, CDC25B, and Aurora B Kinase. We have shown that hypoxia, a well-known stimulus for pulmonary hypertension (PH), induces FoxM1 in pulmonary artery smooth muscle cells (PASMC) in a HIF-dependent pathway, resulting in PASMC proliferation, while the suppression of FoxM1 prevents hypoxia-induced PASMC proliferation. However, the implications of FoxM1 in the development of PH remain less known.
- Qian, Z., Liu, H., Li, M., Shi, J., Li, N., Zhang, Y., Zhang, X., Lv, J., Xie, X., Bai, Y., Ge, Q., Ko, E. A., Tang, H., Wang, T., Wang, X., Wang, Z., Zhou, T., & Gu, W. (2018). Potential Diagnostic Power of Blood Circular RNA Expression in Active Pulmonary Tuberculosis. EBioMedicine, 27, 18-26.More infoCircular RNAs (circRNAs) are a class of novel RNAs with important biological functions, and aberrant expression of circRNAs has been implicated in human diseases. However, the feasibility of using blood circRNAs as disease biomarkers is largely unknown.
- Shu, J., Lu, W., Yang, K., Zheng, Q., Li, D., Li, Y., Kuang, M., Liu, H., Li, Z., Chen, Y., Zhang, C., Luo, X., Huang, J., Wu, X., Tang, H., & Wang, J. (2018). Establishment and evaluation of chronic obstructive pulmonary disease model by chronic exposure to motor vehicle exhaust combined with lipopolysaccharide instillation. Experimental physiology, 103(11), 1532-1542.More infoWhat is the central question of this study? In this study, by using motor vehicle exhaust (MVE) exposure with or without lipopolysaccharide (LPS) instillation, we established, evaluated and compared MVE, LPS and MVE+LPS treatment-induced chronic obstructive pulmonary disease (COPD) models in mice. What is the main finding and its importance? Our study demonstrated that the combination of chronic exposure to MVE with early LPS instillation can establish a mouse model with some features of COPD, which will allow researchers to investigate the underlying molecular mechanisms linking air pollution and COPD pathogenesis.
- Tang, H., Babicheva, A., McDermott, K. M., Gu, Y., Ayon, R. J., Song, S., Wang, Z., Gupta, A., Zhou, T., Sun, X., Dash, S., Wang, Z., Balistrieri, A., Zheng, Q., Cordery, A. G., Desai, A. A., Rischard, F., Khalpey, Z., Wang, J., , Black, S. M., et al. (2018). Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. American journal of physiology. Lung cellular and molecular physiology, 314(2), L256-L275.More infoPulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVECs from patients with IPAH and animals with experimental PH compared with normal controls. LVECs isolated from IPAH patients had a higher level of HIF-2α than that from normal subjects, whereas HIF-1α was upregulated in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase that promotes HIF-2α degradation, was involved in enhanced EndMT and upregulated SNAI1/2 in LVECs from patients with IPAH. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1 and SNAI2 expression in IPAH-LVECs. Mice with endothelial cell (EC)-specific knockout (KO) of the PHD2 gene, egln1 (egln1), developed severe PH under normoxic conditions, whereas Snai1/2 and EndMT were increased in LVECs of egln1 mice. EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48-72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.
- Tang, H., Wu, K., Wang, J., Vinjamuri, S., Gu, Y., Song, S., Wang, Z., Zhang, Q., Balistrieri, A., Ayon, R. J., Rischard, F., Vanderpool, R., Chen, J., Zhou, G., Desai, A. A., Black, S. M., Garcia, J. G., Yuan, J. X., & Makino, A. (2018). Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension. JACC. Basic to translational science, 3(6), 744-762.More infoConcentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.
- Shu, J., Li, D., Ouyang, H., Huang, J., Long, Z., Liang, Z., Chen, Y., Chen, Y., Zheng, Q., Kuang, M., Tang, H., Wang, J., & Lu, W. (2017). Comparison and evaluation of two different methods to establish the cigarette smoke exposure mouse model of COPD. Scientific reports, 7(1), 15454.More infoAnimal model of cigarette smoke (CS) -induced chronic obstructive pulmonary disease (COPD) is the primary testing methodology for drug therapies and studies on pathogenic mechanisms of disease. However, researchers have rarely run simultaneous or side-by-side tests of whole-body and nose-only CS exposure in building their mouse models of COPD. We compared and evaluated these two different methods of CS exposure, plus airway Lipopolysaccharides (LPS) inhalation, in building our COPD mouse model. Compared with the control group, CS exposed mice showed significant increased inspiratory resistance, functional residual capacity, right ventricular hypertrophy index, and total cell count in BALF. Moreover, histological staining exhibited goblet cell hyperplasia, lung inflammation, thickening of smooth muscle layer on bronchia, and lung angiogenesis in both methods of CS exposure. Our data indicated that a viable mouse model of COPD can be established by combining the results from whole-body CS exposure, nose-only CS exposure, and airway LPS inhalation testing. However, in our study, we also found that, given the same amount of particulate intake, changes in right ventricular pressure and intimal thickening of pulmonary small artery are a little more serious in nose-only CS exposure method than changes in the whole-body CS exposure method.
- Tang, H., Zheng, Q., & Wang, J. (2017). Pathogenic role of ion channels in pulmonary arterial hypertension. Experimental physiology, 102(9), 1075-1077.
- Vanderpool, R. R., Tang, H., Rischard, F., & Yuan, J. X. (2017). Is p38 MAPK a Dark Force in Right Ventricular Hypertrophy and Failure in Pulmonary Arterial Hypertension?. American journal of respiratory cell and molecular biology, 57(5), 506-508.
- Wang, J., Xu, C., Zheng, Q., Yang, K., Lai, N., Wang, T., Tang, H., & Lu, W. (2017). Orai1, 2, 3 and STIM1 promote store-operated calcium entry in pulmonary arterial smooth muscle cells. Cell death discovery, 3, 17074.More infoPrevious studies have demonstrated that besides the classic canonical transient receptor potential channel family, Orai family and stromal interaction molecule 1 (STIM1) might also be involved in the regulation of store-operated calcium channels (SOCCs). An increase in cytosolic free Ca concentration promoted by store-operated Ca entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs) is a major trigger for pulmonary vasoconstriction and proliferation and migration of PASMCs. In this study, our data revealed the following: (1) in both rat distal pulmonary arteries and PASMCs, chronic hypoxia exposure upregulated the expression of Orai1 and Orai2, without affecting Orai3 and STIM1; (2) either heterozygous knockout of HIF-1 in mice or knockdown of HIF-1 in PASMCs abolished the hypoxic upregulation of Orai2, but not Orai1, suggesting the hypoxic upregulation of Orai2 depends on HIF-1; and (3) using small interference RNA knockdown strategies, Orai1, 2, 3 and STIM1 were all shown to mediate SOCE in hypoxic PASMCs. Together, these results suggested that the components of SOCCs, including Orai1, 2, 3 and STIM1, may lead to novel therapeutic targets for the treatment of chronic hypoxia-induced pulmonary hypertension.
- Ayon, R. J., Tang, H., & Yuan, J. X. (2016). Gasping for answers. Focus on "Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia". American journal of physiology. Cell physiology, 310(6), C432-3.
- Chen, T., Zhou, Q., Tang, H., Bozkanat, M., Yuan, J. X., Raj, J. U., & Zhou, G. (2016). miR-17/20 Controls Prolyl Hydroxylase 2 (PHD2)/Hypoxia-Inducible Factor 1 (HIF1) to Regulate Pulmonary Artery Smooth Muscle Cell Proliferation. Journal of the American Heart Association, 5(12).More infoPreviously we found that smooth muscle cell (SMC)-specific knockout of miR-17~92 attenuates hypoxia-induced pulmonary hypertension. However, the mechanism underlying miR-17~92-mediated pulmonary artery SMC (PASMC) proliferation remains unclear. We sought to investigate whether miR-17~92 regulates hypoxia-inducible factor (HIF) activity and PASMC proliferation via prolyl hydroxylases (PHDs).
- Jiang, Q., Lu, W., Yang, K., Hadadi, C., Fu, X., Chen, Y., Yun, X., Zhang, J., Li, M., Xu, L., Tang, H., Yuan, J. X., Wang, J., & Sun, D. (2016). Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis. American journal of physiology. Cell physiology, 311(1), C136-49.More infoOur laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited store-operated Ca(2+) entry (SOCE) through store-operated Ca(2+) channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125-134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231-240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxia-mediated inhibition of the PKG-PPAR-γ signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-γ. Moreover, targeted PPAR-γ agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-γ signaling pathway in PASMCs.
- Song, S., Ayon, R. J., Yamamura, A., Yamamura, H., Dash, S., Babicheva, A., Tang, H., Sun, X., Cordery, A. G., Khalpey, Z. I., Black, S. M., Desai, A. A., Rischard, F., McDermott, K. M., Garcia, J. G., Makino, A., & Yuan, J. X. (2016). Capsaicin-induced Ca2+ Signaling is Enhanced via Upregulated TRPV1 Channels in Pulmonary Artery Smooth Muscle Cells from Patients with Idiopathic PAH. American journal of physiology. Lung cellular and molecular physiology, ajplung.00357.2016.More infoCapsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23ºC to 43ºC, or decreasing extracellular pH value from 7.4 to 5.9, enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43ºC)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing extracellular osmotic pressure from 310 to 200 mOsmol/L also increased [Ca2+]cyt and the hypoosmolarity-induced rise in [Ca2+]cyt was greater in IPAH PASMCs than in normal PASMCs. Inhibition of TRPV1 (with 5'-IRTX or capsazepine) or knockdown of TRPV1 (with shRNA) attenuated capsaicin-, acidity- and osmotic stretch-mediated [Ca2+]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt; the capsaicin-induced CREB phosphorylation was significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMCs proliferation. Taken together, the capsaicin-mediated [Ca2+]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism contributing to the augmented Ca2+ influx and excessive PASMCs proliferation in IPAH patients.
- Song, S., Jacobson, K. N., McDermott, K. M., Reddy, S. P., Cress, A. E., Tang, H., Dudek, S. M., Black, S. M., Garcia, J. G., Makino, A., & Yuan, J. X. (2016). ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells. American journal of physiology. Cell physiology, 310(2), C99-C114.More infoAdenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca(2+) signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca(2+)] ([Ca(2+)]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca(2+) eliminated the plateau phase increase of [Ca(2+)]cyt in lung cancer cells, indicating that the plateau phase of [Ca(2+)]cyt increase is due to Ca(2+) influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca(2+) or chelating intracellular Ca(2+) with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca(2+)]cyt through Ca(2+) influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression.
- Tang, H., Desai, A. A., & Yuan, J. X. (2016). Genetic Insights into Pulmonary Arterial Hypertension. Application of Whole-Exome Sequencing to the Study of Pathogenic Mechanisms. American journal of respiratory and critical care medicine, 194(4), 393-7.
- Tang, H., Yamamura, A., Yamamura, H., Song, S., Fraidenburg, D. R., Chen, J., Gu, Y., Pohl, N. M., Zhou, T., Jiménez-Pérez, L., Ayon, R. J., Desai, A. A., Goltzman, D., Rischard, F., Khalpey, Z. I., Black, S. M., Garcia, J. G., Makino, A., & Yuan, J. X. (2016). Pathogenic Role of Calcium-sensing Receptors in the Development and Progression of Pulmonary Hypertension. American journal of physiology. Lung cellular and molecular physiology, ajplung.00050.2016.More infoAn increase in [Ca(2+)]cyt in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. We previously demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with IPAH and animals with experimental PH were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca(2+) influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here we report that CaSR functionally interacts with TRPC6 to regulate [Ca(2+)]cyt in PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca2(+-)induced [Ca(2+)]cyt increase in IPAH-PASMC (in which CaSR is upregulated), while overexpression of CaSR or TRPC6 enhanced Ca2(+-)induced [Ca(2+)]cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, while blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice (casr(-/-)) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.
- Zhang, J., Lu, W., Chen, Y., Jiang, Q., Yang, K., Li, M., Wang, Z., Duan, X., Xu, L., Tang, H., Sun, D., & Wang, J. (2016). Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs. American journal of physiology. Cell physiology, 311(3), C482-97.More infoThe ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca(2+)] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca(2+)]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca(2+)]i signaling axis in PASMCs.
- Chen, T., Zhou, G., Zhou, Q., Tang, H., Ibe, J. C., Cheng, H., Gou, D., Chen, J., Yuan, J. X., & Raj, J. U. (2015). Loss of microRNA-17∼92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. American journal of respiratory and critical care medicine, 191(6), 678-92.More infoRecent studies suggest that microRNAs (miRNAs) play important roles in regulation of pulmonary artery smooth muscle cell (PASMC) phenotype and are implicated in pulmonary arterial hypertension (PAH). However, the underlying molecular mechanisms remain elusive.
- Fernandez, R. A., Wan, J., Song, S., Smith, K. A., Gu, Y., Tauseef, M., Tang, H., Makino, A., Mehta, D., & Yuan, J. X. (2015). Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. American journal of physiology. Cell physiology, 308(8), C581-93.More infoPulmonary arterial hypertension (PAH) is a progressive disease that, if left untreated, eventually leads to right heart failure and death. Elevated pulmonary arterial pressure (PAP) in patients with PAH is mainly caused by an increase in pulmonary vascular resistance (PVR). Sustained vasoconstriction and excessive pulmonary vascular remodeling are two major causes for elevated PVR in patients with PAH. Excessive pulmonary vascular remodeling is mediated by increased proliferation of pulmonary arterial smooth muscle cells (PASMC) due to PASMC dedifferentiation from a contractile or quiescent phenotype to a proliferative or synthetic phenotype. Increased cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in PASMC is a key stimulus for cell proliferation and this phenotypic transition. Voltage-dependent Ca(2+) entry (VDCE) and store-operated Ca(2+) entry (SOCE) are important mechanisms for controlling [Ca(2+)]cyt. Stromal interacting molecule proteins (e.g., STIM2) and Orai2 both contribute to SOCE and we have previously shown that STIM2 and Orai2, specifically, are upregulated in PASMC from patients with idiopathic PAH and from animals with experimental pulmonary hypertension in comparison to normal controls. In this study, we show that STIM2 and Orai2 are upregulated in proliferating PASMC compared with contractile phenotype of PASMC. Additionally, a switch in Ca(2+) regulation is observed in correlation with a phenotypic transition from contractile PASMC to proliferative PASMC. PASMC in a contractile phenotype or state have increased VDCE, while in the proliferative phenotype or state PASMC have increased SOCE. The data from this study indicate that upregulation of STIM2 and Orai2 is involved in the phenotypic transition of PASMC from a contractile state to a proliferative state; the enhanced SOCE due to upregulation of STIM2 and Orai2 plays an important role in PASMC proliferation.
- Gong, H., Rehman, J., Tang, H., Wary, K., Mittal, M., Chaturvedi, P., Zhao, Y. Y., Chatturvedi, P., Zhao, Y., Komarova, Y. A., Komorova, Y. A., Vogel, S. M., & Malik, A. B. (2015). HIF2α signaling inhibits adherens junctional disruption in acute lung injury. The Journal of clinical investigation, 125(2), 652-64.More infoVascular endothelial barrier dysfunction underlies diseases such as acute respiratory distress syndrome (ARDS), characterized by edema and inflammatory cell infiltration. The transcription factor HIF2α is highly expressed in vascular endothelial cells (ECs) and may regulate endothelial barrier function. Here, we analyzed promoter sequences of genes encoding proteins that regulate adherens junction (AJ) integrity and determined that vascular endothelial protein tyrosine phosphatase (VE-PTP) is a HIF2α target. HIF2α-induced VE-PTP expression enhanced dephosphorylation of VE-cadherin, which reduced VE-cadherin endocytosis and thereby augmented AJ integrity and endothelial barrier function. Mice harboring an EC-specific deletion of Hif2a exhibited decreased VE-PTP expression and increased VE-cadherin phosphorylation, resulting in defective AJs. Mice lacking HIF2α in ECs had increased lung vascular permeability and water content, both of which were further exacerbated by endotoxin-mediated injury. Treatment of these mice with Fg4497, a prolyl hydroxylase domain 2 (PHD2) inhibitor, activated HIF2α-mediated transcription in a hypoxia-independent manner. HIF2α activation increased VE-PTP expression, decreased VE-cadherin phosphorylation, promoted AJ integrity, and prevented the loss of endothelial barrier function. These findings demonstrate that HIF2α enhances endothelial barrier integrity, in part through VE-PTP expression and the resultant VE-cadherin dephosphorylation-mediated assembly of AJs. Moreover, activation of HIF2α/VE-PTP signaling via PHD2 inhibition has the potential to prevent the formation of leaky vessels and edema in inflammatory diseases such as ARDS.
- Gong, H., Rehman, J., Tang, H., Wary, K., Mittal, M., Chaturvedi, P., Zhao, Y., Komarova, Y. A., Vogel, S. M., & Malik, A. B. (2015). Corrigendum. HIF2α signaling inhibits adherens junctional disruption in acute lung injury. The Journal of clinical investigation, 125(3), 1364.
- Smith, K. A., Voiriot, G., Tang, H., Fraidenburg, D. R., Song, S., Yamamura, H., Yamamura, A., Guo, Q., Wan, J., Pohl, N. M., Tauseef, M., Bodmer, R., Ocorr, K., Thistlethwaite, P. A., Haddad, G. G., Powell, F. L., Makino, A., Mehta, D., & Yuan, J. X. (2015). Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension. American journal of respiratory cell and molecular biology, 53(3), 355-67.More infoHypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca(2+) entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wild-type and canonical transient receptor potential (TRPC) 6(-/-) mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca(2+) concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia.
- Tang, H., Ayon, R. J., & Yuan, J. X. (2015). New insights into the pathology of pulmonary hypertension: implication of the miR-210/ISCU1/2/Fe-S axis. EMBO molecular medicine, 7(6), 689-91.More infoElevated pulmonary arterial pressure in patients with pulmonary hypertension (PH) is mainly caused by increased pulmonary vascular resistance (PVR), due primarily to sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling. According to the current classification, PH has been classified into five categories based on etiology (Simonneau et al, 2013). Among them, group 1 or pulmonary arterial hypertension (PAH) is a rare but progressive and deadly disease affecting ~1–10 per 1 million people. Despite expanding treatment options to ameliorate patients' symptoms, PAH remains a devastating disease with a poor long‐term prognosis.
- Tang, H., Chen, J., Fraidenburg, D. R., Song, S., Sysol, J. R., Drennan, A. R., Offermanns, S., Ye, R. D., Bonini, M. G., Minshall, R. D., Garcia, J. G., Machado, R. F., Makino, A., & Yuan, J. X. (2015). Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology, 308(2), L208-20.More infoPulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1-3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1(-/-) mice were protected against the development and progression of chronic HPH, whereas Akt2(-/-) mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1(-/-) mice, with no significant effect noted in the Akt2(-/-) mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.
- Tang, H., Fernandez, R. A., & Yuan, J. X. (2015). miRNA208/Mef2 and TNF-α in right ventricular dysfunction: the transition from hypertrophy to failure. Circulation research, 116(1), 6-8.
- Chen, J., Tang, H., Sysol, J. R., Moreno-Vinasco, L., Shioura, K. M., Chen, T., Gorshkova, I., Wang, L., Huang, L. S., Usatyuk, P. V., Sammani, S., Zhou, G., Raj, J. U., Garcia, J. G., Berdyshev, E., Yuan, J. X., Natarajan, V., & Machado, R. F. (2014). The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension. American journal of respiratory and critical care medicine, 190(9), 1032-43.More infoSphingosine kinases (SphKs) 1 and 2 regulate the synthesis of the bioactive sphingolipid sphingosine-1-phosphate (S1P), an important lipid mediator that promotes cell proliferation, migration, and angiogenesis.
- Song, S., Yamamura, A., Yamamura, H., Ayon, R. J., Smith, K. A., Tang, H., Makino, A., & Yuan, J. X. (2014). Flow shear stress enhances intracellular Ca2+ signaling in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension. American journal of physiology. Cell physiology, 307(4), C373-83.More infoAn increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for pulmonary arterial medial hypertrophy in patients with idiopathic pulmonary arterial hypertension (IPAH). Vascular smooth muscle cells (SMC) sense the blood flow shear stress through interstitial fluid driven by pressure or direct exposure to blood flow in case of endothelial injury. Mechanical stimulus can increase [Ca(2+)]cyt. Here we report that flow shear stress raised [Ca(2+)]cyt in PASMC, while the shear stress-mediated rise in [Ca(2+)]cyt and the protein expression level of TRPM7 and TRPV4 channels were significantly greater in IPAH-PASMC than in normal PASMC. Blockade of TRPM7 by 2-APB or TRPV4 by Ruthenium red inhibited shear stress-induced rise in [Ca(2+)]cyt in normal and IPAH-PASMC, while activation of TRPM7 by bradykinin or TRPV4 by 4αPDD induced greater increase in [Ca(2+)]cyt in IPAH-PASMC than in normal PASMC. The bradykinin-mediated activation of TRPM7 also led to a greater increase in [Mg(2+)]cyt in IPAH-PASMC than in normal PASMC. Knockdown of TRPM7 and TRPV4 by siRNA significantly attenuated the shear stress-mediated [Ca(2+)]cyt increases in normal and IPAH-PASMC. In conclusion, upregulated mechanosensitive channels (e.g., TRPM7, TRPV4, TRPC6) contribute to the enhanced [Ca(2+)]cyt increase induced by shear stress in PASMC from IPAH patients. Blockade of the mechanosensitive cation channels may represent a novel therapeutic approach for relieving elevated [Ca(2+)]cyt in PASMC and thereby inhibiting sustained pulmonary vasoconstriction and pulmonary vascular remodeling in patients with IPAH.
- Zimnicka, A. M., Tang, H., Guo, Q., Kuhr, F. K., Oh, M. J., Wan, J., Chen, J., Smith, K. A., Fraidenburg, D. R., Choudhury, M. S., Levitan, I., Machado, R. F., Kaplan, J. H., & Yuan, J. X. (2014). Upregulated copper transporters in hypoxia-induced pulmonary hypertension. PloS one, 9(3), e90544.More infoPulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.
- Smith, K. A., Ayon, R. J., Tang, H., Makino, A., & Yuan, J. X. (2016. Calcium-Sensing Receptor Regulates Cytosolic [Ca (2+) ] and Plays a Major Role in the Development of Pulmonary Hypertension(p. 517).More infoPulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance (PVR) leading to right heart failure and premature death. The increased PVR results in part from pulmonary vascular remodeling and sustained pulmonary vasoconstriction. Excessive pulmonary vascular remodeling stems from increased pulmonary arterial smooth muscle cell (PASMC) proliferation and decreased PASMC apoptosis. A rise in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in PASMC is a major trigger for pulmonary vasoconstriction and a key stimulus for PASMC proliferation and migration, both contributing to the development of pulmonary vascular remodeling. PASMC from patients with idiopathic PAH (IPAH) have increased resting [Ca(2+)]cyt and enhanced Ca(2+) influx. Enhanced Ca(2+) entry into PASMC due to upregulation of membrane receptors and/or Ca(2+) channels may contribute to PASMC contraction and proliferation and to pulmonary vasoconstriction and pulmonary vascular remodeling. We have shown that the extracellular Ca(2+)-sensing receptor (CaSR), which is a member of G protein-coupled receptor (GPCR) subfamily C, is upregulated, and the extracellular Ca(2+)-induced increase in [Ca(2+)]cyt is enhanced in PASMC from patients with IPAH in comparison to PASMC from normal subjects. Pharmacologically blockade of CaSR significantly attenuate the development and progression of experimental pulmonary hypertension in animals. Additionally, we have demonstrated that dihydropyridine Ca(2+) channel blockers (e.g., nifedipine), which are used to treat PAH patients but are only effective in 15-20% of patients, activate CaSR resulting in an increase in [Ca(2+)]cyt in IPAH-PASMC, but not normal PASMC. Our data indicate that CaSR functionally couples with transient receptor potential canonical (TRPC) channels to mediate extracellular Ca(2+)-induced Ca(2+) influx and increase in [Ca(2+)]cyt in IPAH-PASMC. Upregulated CaSR is necessary for the enhanced extracellular Ca(2+)-induced increase in [Ca(2+)]cyt and the augmented proliferation of PASMC in patients with IPAH. This review will highlight the pathogenic role of CaSR in the development and progression of PAH.
- Babicheva, A., Mcdermott, K. M., Ayon, R., Dash, S., Tang, H., Cordery, A. G., Desai, A., Black, S., Garcia, J. G., Makino, A., & Yuan, J. (2016, October). Role of endothelial-to-mesenchymal transition associated with PHD2/HIF1α/2α pathway in the progression of idiopathic pulmonary arterial hypertension. Arizona Physiological Society meeting.
- Babivheva, A., Mcdermott, K. M., Sun, S., Song, S., Tang, H., Cordery, A. G., Desai, A., Black, S., Garcia, J. G., Makino, A., & Yuan, J. (2016, June). Inhibition of PHD2 Induces Endothelial-to-Mesenchymal Transition in Pulmonary Vascular Endothelial Cells..
- Song, S., Yamamura, A., Yamamura, H., Babicheva, A., Tang, H., Ayon, R., Mcdermott, K. M., Sun, X., Black, S., Makino, A., & Yuan, J. (2016, April). Hot, Heat and Stretch All Contribute to the Enhanced Ca2+ Signaling in Pulmonary Arterial Hypertension. The FASEB Journal.