PKC Signaling in cAMP-Induced Pulmonary Vasodilation

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date7/1/0112/31/11

ASJC

  • Medicine(all)