The objective of this proposal is to test the hypothesis that activation of specific PKC isoform(s) is a major step in a signal transduction cascade leading to maintained contraction of coronary smooth muscle.
The specific aims are: 1) to identify the Ca2+-dependent and Ca2+-independent isoforms of PKC expressed in coronary smooth muscle; 2) to determine the subcellular distribution of PKC isoforms in resting and activated coronary smooth muscle cells; 3) to determine the physiological intracellular Ca2+ requirement for activation and translocation of PKC isoforms in situ; 4) to determine whether activation of specific PKC isoforms(s) and contraction of coronary smooth muscle have a cause-and-effect relationship; and 5) to determine whether specific PKC isoforms are overly expressed or hyperactive in coronary smooth muscle of animal models of coronary vasospasm. These studies aim to provide an understanding of the cellular mechanisms underlying coronary smooth muscle contraction and a possible pathophysiological basis of coronary vasospasm.
