Protein kinase C (PKC) has a central role in the process of signal transduction. In vascular smooth muscle (VSM), PKC has been hypothesized to be involved in the regulation of tonic contraction in a manner distinct from known mechanisms involving regulation of crossbridge activity by phosphorylation of the 20 kilodalton regulatory light chains of myosin. One of the general goals of the proposed research has been to determine whether PKC can be regulated by contractile stimuli in VSM, and if so, to identify specific substrates that are phosphorylated and the functional consequences of this. The studies to date support the concept that contractile stimuli can cause a prolonged activation of PKC in intact arterial smooth muscle. This is based on the measurement of PKC activity associated with membrane fractions isolated from stimulated tissues. It is also clear that other functions linked to PKC activations, for example those related to regulation of cell shape, specific gene expression, and growth are likely to be important from the standpoint of both normal VSM cell physiology and VSM cell pathophysiology. Additional approaches in a model system of cultured rat aortic smooth muscle are proposed to; 1) define the specific isozymes of PKC which are expressed in VSM, their activation properties, and subcellular distribution, 2) determine whether contractile and growth stimuli can alter the abundance and/or activity of specific isozymes in discrete subcellular fractions, and 3) assess the functional consequences of this activation in specific subcellular compartments. Protein kinase C activities have been shown to be elevated in some tissues from hypertensive subjects, and is the receptor for tumor promotor such as phorbol esters. Details regarding this aspect of signal transduction in VSM is likely to be of importance in understanding pathology associated with vascular diseases in which contractile activity is altered, such as hypertension and vasospasm, or in which VSM cell growth is altered, such as atherosclerosis.
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