DESCRIPTION (provided by applicant): 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.
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