EXERCISE, DIABETES, & CORONARY SMOOTH MUSCLE Ca2+

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DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the extent to which exercise training decreases coronary artery disease (CAD) after stenting in diabetes and the coronary smooth muscle (CSM) Ca signaling mechanisms involved. We propose that CAD progression in non-stented conduits and/or microvascular dysfunction may contribute to the increased mortality after coronary stenting in diabetes. We have shown that Diabetic Dyslipidemic (DD) pigs have accelerated coronary atheroma, thus making it feasible to stent natural atherosclerotic lesions, not balloon-injured healthy arteries. Overall hypothesis: exercise-induced change in Ca localization is a pivotal signal to attenuate increased growth of conduit CSM and contraction of microvascular CSM after stenting in DD. Overall experimental design: coronary stents are placed in low fat fed healthy controls (C), high fat/cholesterol fed hyperlipidemic and atherosclerotic (H), diabetic dyslipidemic and atherosclerotic (DD), and DD pigs that are aerobically exercise trained (DDX). Specific Aims are to test the hypotheses that in DD, compared to non-diabetics (H), after Iong-ter m recovery from stenting: 1) In-stent restenosis is not increased; instead, progression of CAD in non-stented cohduits and microvascular dysfunction are increased and both are prevented by exercise. Intravascular ultrasound will provide high spatial resolution of in vivo morphology and intravascular Doppler FIoWires will assess microvascular dysfunction. 2) Progression of CAD in non-stented conduits, but not microvascular dysfunction, is directly related to increased coronary endothelin and smooth muscle growth, which are prevented by exercise. Histology will determine the extent of intimal thickening and endothelin content in conduits. HPLC measures of coronary artery lipids will complement histology to determine whether DD have more cellular lesions than H. 3) Progression of CAD in non-stented conduits is directly related to increased tyrosine kinase, Can., and Kca current, which are prevented by exercise. Single cell tyrosine phosphorylation, distribution of Ca stores, and nuclear Ca (Ca/n) will be measured with confocal microscopy. Ca-dependent K currents (Kca) will be measured with patch clamp. 4) Microvascular dysfunction involves no change in Can, but is directly related to decreased Kca current, which is prevented by exercise. Functional Ca release is at the sarcolemma eliciting Kca, hyperpolarization, and relaxation in C, while Kca decreases in DD. Significance of this research is the relation of clinical and functional endpoints (Aims 1,2) to the differences in Ca localization mechanisms (Aims 3,4) of the therapeutic effects of exercise on conduit vs. microvascular CSM in diabetic dyslipidemia.