PKC Signaling in cAMP-Induced Pulmonary Vasodilation

cAMP 诱导的肺血管舒张中的 PKC 信号转导

• 批准号: 6538070
• 负责人: Scott A Barman
• 金额: $ 25.11万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6538070
• 关键词: cGMP dependent protein kinase; cyclic AMP; disease /disorder model; enzyme activity; laboratory rat; potassium channel; protein kinase C; pulmonary artery; pulmonary hypertension; vascular smooth muscle; vasodilators; vasomotion; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：原发性肺动脉高压（PPH）是一种疾病