Ion Channel Regulation Coronary Smooth Muscle Phenotype

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