Idiopathic Pulmonary Arterial Hypertension (IPAH) is a disease of unknown origin that results in narrowing of the pulmonary arteries causing high pulmonary blood pressure often leading to heart failure. Currently, there is little knowledge on the cellular and molecular foundation of IPAH. Normally, signaling mechanisms which elevate cAMP and cGMP in the pulmonary vasculature maintain a low pressure, high perfusion environment. Activation of large-conductance, calcium- and voltage-activated potassium (BKCa) channels is important in the regulation of pulmonary arterial pressure and inhibition of BKCa channels has been implicated in pulmonary hypertension. Published studies from our laboratory in pulmonary arterial smooth muscle cells (PASMC) of the Fawn-Hooded rat (FHR), an animal model of pulmonary hypertension, show that cAMP, an activator of cAMP-dependent protein kinase (PKA), opens BKCa channels through """"""""cross-activation"""""""" of cGMP-dependent protein kinase (PKG), which is inhibited by protein kinase C (PKC) activators. In contrast, PKC activation opens BKCa channels in (normotensive control) PASMC of Sprague-Dawley rats (SDR). New preliminary data indicate that specific PKC isozymes are differentially expressed in normotensive and hypertensive PASMC, and that PKC and PKG regulation of BKCa channel activity requires the expression and phosphorylation of specific sites on BKCa channel subunits. Therefore, the hypothesis of the proposed studies is that specific PKC isozymes differentially regulate BKCa channel activity in normotensive and hypertensive pulmonary arterial smooth muscle via targeted PKC and PKG phosphorylation sites on BKCa channel subunits. This hypothesis will be tested using current techniques of electrophysiology, vascular contraction, and biochemistry/molecular biology to determine in normotensive and hypertensive PASMC: 1) mechanisms of PKC regulation of BKCa channels, 2) the relationship of BKCa channel subunit expression to protein kinase (PKA, PKC, PKG)-mediated function, and 3) mechanisms of phosphorylating specific subunit sites that elicit regulatory effects of PKA, PKC and PKG on BKCa channel activity. The long-term goal is to determine how PKC regulates the effect of cAMP-elevating agents in pulmonary arterial smooth muscle. Progress of these studies will provide important knowledge towards the development of novel therapeutic agents that will help reduce the morbidity and mortality associated with pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068026-08
Application #
7802249
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2001-07-01
Project End
2011-12-31
Budget Start
2010-04-01
Budget End
2011-12-31
Support Year
8
Fiscal Year
2010
Total Cost
$330,750
Indirect Cost
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Barman, Scott A; Chen, Feng; Su, Yunchao et al. (2014) NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arterioscler Thromb Vasc Biol 34:1704-15
Yu, Xuan; Ma, Handong; Barman, Scott A et al. (2011) Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle. Am J Physiol Endocrinol Metab 301:E882-8
White, Richard E; Gerrity, Ross; Barman, Scott A et al. (2010) Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women. Steroids 75:788-93
Zhu, Shu; Browning, Darren D; White, Richard E et al. (2009) Mutation of protein kinase C phosphorylation site S1076 on alpha-subunits affects BK(Ca) channel activity in HEK-293 cells. Am J Physiol Lung Cell Mol Physiol 297:L758-66
Han, Guichun; Ma, Handong; Chintala, Rajesh et al. (2009) Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle. J Pharmacol Exp Ther 329:850-5
Barman, Scott A; Zhu, Shu; White, Richard E (2009) RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension. Vasc Health Risk Manag 5:663-71
Zhu, Shu; White, Richard E; Barman, Scott A (2008) Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle. Ther Adv Respir Dis 2:119-27
Han, Guichun; Ma, Handong; Chintala, Rajesh et al. (2007) Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling. Am J Physiol Heart Circ Physiol 293:H314-21
Barman, Scott A (2007) Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C. Am J Physiol Lung Cell Mol Physiol 293:L472-9
Zhu, Shu; White, Richard E; Barman, Scott A (2006) Effect of PKC isozyme inhibition on forskolin-induced activation of BKCa channels in rat pulmonary arterial smooth muscle. Lung 184:89-97

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