Ion Channel Regulation Coronary Smooth Muscle Phenotype

$273,016P01FY2006HLNIH

University Of Missouri-Columbia, Columbia MO

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Abstract

It is becoming increasingly evident that calcium influx in vascular smooth muscle is a strong modulator of[unreadable] smooth muscle (SM) gene regulation and phenotype via activation of calcium-dependent transcription[unreadable] factors. We provide evidence that L-type calcium influx is necessary for the constitutive expression of[unreadable] smooth muscle-specific differentiation markers (SMX: e.g. SMMHC, SMaA) and that exercise can increase[unreadable] L-type calcium channel function in coronary smooth muscle (CSM). The general aim of this proposal is to[unreadable] determine the mechanism(s) by which exercise training limits CSM phenotype switching during[unreadable] atherosclerosis. The overall hypothesis is that calcium influx via L-type, voltage-gated calcium channels (L-VGCC)[unreadable] stabilizes CSM in a differentiated, contractile phenotype. Conversely, dedifferentiation and[unreadable] proliferation are stimulated by upregulation of intermediate-conductance K channels (IK) and store-operated[unreadable] calcium channels (SOC). Exercise training prevents CSM phenotypic switching by maintaining L-VGCC[unreadable] activity and subsequent SM-specific, calcium-dependent gene expression. The Specific Aims are:1)[unreadable] Determine the effect of atherosclerosis on CSM ion channel functional expression, 2) Determine the effect of[unreadable] atherosclerosis on intracellular calicum regulation by membrane potential, 3) Determine the effect of L-type[unreadable] VGCC- versus IK/SOC-mediated calcium influx on calcium-dependent transcription factors and SMX and 4)[unreadable] Determine whether exercise training can prevent the loss of L-type VGCC-mediated SMX. Early and[unreadable] advanced models of atherosclerosis will be produced in swine by dietary high-fat, high-cholesterol (HFC) or[unreadable] balloon injury. Both in vitro and in vivo measures of CSM phenotype will be determined using molecular,[unreadable] cellular and in vivo coronary angiography techniques. The proposed research will provide the first[unreadable] mechanistic link between coronary ion channel activity and CSM phenotype switching. Furthermore, it will[unreadable] provide the first mechanistic examination of the role of CSM in the cardioprotective effect of exercise.

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