In patients with chronic thromboembolic pulmonary hypertension (CTEPH), elevated pulmonary vascular resistance (PVR) is caused by obstruction of proximal and distal pulmonary arteries with thromboemboli, and by pulmonary vascular remodeling due to excessive migration and proliferation of pulmonary vascular smooth muscle (PASMC) and endothelial (PAEC) cells. The thromboemboli attached to the pulmonary vascular wall include a large amount of blood coagulation factors (e.g., thrombin, fibrinogen), which may serve as triggers for vascular remodeling. A rise in cytosolic [Ca2+] in PAEC induced by thrombin increases endothelial permeability, which allows mitogenic factors to penetrate into the vascular media and cause medial hypertrophy. A rise in cytosolic [Ca2+] in PASMC stimulates cell proliferation by upregulating Ca2+- sensitive signaling proteins and transcription factors. By activating receptors in PASMC, the coagulation factors (e.g., thrombin and fibrinogen) also cause increases in cytosolic [Ca2+] by promoting Ca2+ influx through transient receptor potential (TRP) channels. We have recently demonstrated that a) TRP expression is increased and Ca2+ entry through TRP channels is augmented in normal PASMC during proliferation, b) inhibition of TRP expression with siRNA attenuates PASMC proliferation, c) mRNA and protein expression of TRP (e.g., TRPC3/6) is upregulated in PASMC from patients with idiopathic pulmonary arterial hypertension. Based on these data, we hypothesize that abnormally enhanced gene expression of TRP channels in the pulmonary vasculature serves as a predisposition for thromboemboli-mediated pulmonary vascular remodeling in CTEPH patients.
Three specific aims are proposed to test the hypothesis: 1) To examine whether and which TRP channels are transcriptionally upregulated, and whether TRP-encoded store- and receptor-operated cation channels are functionally enhanced, in PASMC isolated from CTEPH patients;2) To examine whether coagulation factors (thrombin nd fibrinogen) increase cytosolic [Ca2+] by activating TRP channels in PASMC and, if so, which TRP channel subunits are functionally regulated by thrombin and fibrinogen;and 3) To examine whether the mitogenic effect of thrombin and fibrinogen depends on increases in cytosolic [Ca2+] due to Ca2+ entry through TRP channels in normal PASMC and is enhanced in PASMC from CTEPH patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066012-09
Application #
7776934
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Moore, Timothy M
Project Start
2000-12-01
Project End
2010-05-31
Budget Start
2010-02-01
Budget End
2010-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$378,356
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Jiwang; Sysol, Justin R; Singla, Sunit et al. (2017) Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation 135:1532-1546
Tang, Haiyang; Desai, Ankit A; Yuan, Jason X-J (2016) Genetic Insights into Pulmonary Arterial Hypertension. Application of Whole-Exome Sequencing to the Study of Pathogenic Mechanisms. Am J Respir Crit Care Med 194:393-7
Song, Shanshan; Ayon, Ramon J; Yuan, Jason X-J (2016) Ryanodine receptor-2: a necessity for gating store-operated Ca2+ channels. Cardiovasc Res 111:13-5
Tang, Haiyang; Yamamura, Aya; Yamamura, Hisao et al. (2016) Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 310:L846-59
Song, Shanshan; Jacobson, Krista N; McDermott, Kimberly M et al. (2016) ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells. Am J Physiol Cell Physiol 310:C99-114
Fernandez, Ruby A; Wan, Jun; Song, Shanshan et al. (2015) Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am J Physiol Cell Physiol 308:C581-93
Tang, Haiyang; Ayon, Ramon J; Yuan, Jason X-J (2015) New insights into the pathology of pulmonary hypertension: implication of the miR-210/ISCU1/2/Fe-S axis. EMBO Mol Med 7:689-91
Smith, Kimberly A; Voiriot, Guillaume; Tang, Haiyang et al. (2015) Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension. Am J Respir Cell Mol Biol 53:355-67
Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R et al. (2015) Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308:L208-20
Tang, Haiyang; Fernandez, Ruby A; Yuan, Jason X-J (2015) miRNA208/Mef2 and TNF-? in right ventricular dysfunction: the transition from hypertrophy to failure. Circ Res 116:6-8

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