Primary Pulmonary Hypertension (PPH) is a disease of unknown origin that results in narrowing Of the pulmonary vasculature causing high pulmonary blood pressure often leading to heart failure. Currently there is little knowledge on the cellular and molecular foundation of PPH. Normally, signaling mechanisms which elevate cAMP and cGMP in the pulmonary vasculature allow for the maintenance of a low pressure, high perfusion environment. It is well documented that the activation of the large-conductance, calcium-and voltage-activated potassium (BKca) channel is of primary importance in the regulation of pulmonary arterial pressure and inhibition of the BKca channel has been implicated in the development of pulmonary hypertension. Preliminary data from patch-clamp studies in pulmonary arterial smooth muscle cells (PASM) of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension, suggests that cAMP, an activator of cAMP-dependent protein kinase (PKA), opens the BKca channel through """"""""cross-activation"""""""" of the cGMP-dependent protein kinase (PKG). In contrast, protein kinase C (PKC) which causes pulmonary vasoconstriction, inhibits the BKca channel in FHR PASM, but activates the BKca channel in Sprague-Dawley (control) rats. Therefore, the hypothesis of the proposed studies is that cAMP-dependent vasodilators relax pulmonary arteries by opening BKca channels in pulmonary arterial smooth muscle by stimulating the activity of PKG, an effect inhibited by activation of PKC in FHR. This hypothesis will be tested by employing state-of-the-art techniques of electrophysiology, vascular contraction, and biochemistry/molecular biology to determine: 1) the effect of cAMP-dependent vasodilators on pulmonary arteries in vitro, 2) the effect of cAMP-elevating agents on whole-cell and single channel K+ currents from single myocytes isolated from pulmonary arteries, 3) cAMP-dependent """"""""cross-activation"""""""" of PKG, and 4) the role of PKC on BKca channel activity and whether there is a direct interaction between PKG and PKC on BKca channel modulation. The long term goal of the proposed study is to understand how cAMP-elevating agents cause pulmonary arterial vasodilation by an endothelium-independent mechanism. It is believed that these studies will lead to the development of novel therapeutic agents that will help reduce the morbidity and mortality associated with PPH and other pulmonary vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068026-04
Application #
6748442
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
2001-07-01
Project End
2007-03-31
Budget Start
2004-06-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$251,125
Indirect Cost
Name
Medical College of Georgia (MCG)
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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