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CARDIOVASCULAR

Increased Endothelin-Induced Ca²⁺ Signaling, Tyrosine Phosphorylation, and Coronary Artery Disease in Diabetic Dyslipidemic Swine Are Prevented by Atorvastatin

Department of Medical Pharmacology and Physiology (D.L.L., B.R.W., M.S.), Department of Internal Medicine (H.K.R., D.J.V., M.S.), Dalton Cardiovascular Research Center (J.L.D.), Diabetes and Cardiovascular Biology Program (H.K.R., J.L.D., M.S.), University of Missouri, Columbia, Missouri; and Department of Physiology (L.C.K.), Brody School of Medicine, East Carolina University, Greenville, North Carolina

Endothelin-1 (ET-1) signaling mechanisms have been implicated in the pathogenesis of excess coronary artery disease in diabetic dyslipidemia. We hypothesized that in diabetic dyslipidemia ET-1-induced coronary smooth muscle calcium (Ca²⁺_m) and tyrosine phosphorylation would be increased, and the lipid lowering agent, atorvastatin, would inhibit these increases. Male Yucatan miniature swine groups were treated for 20 weeks: normal low-fat fed control, high-fat/cholesterol fed (hyperlipidemic), hyperlipidemic made diabetic with alloxan (diabetic dyslipidemic), and diabetic dyslipidemic treated with atorvastatin (atorvastatin-treated). Blood glucose values were 5-fold greater in diabetic dyslipidemic and atorvastatin-treated versus control and hyperlipidemic. Total and low-density lipoprotein (LDL) plasma cholesterol in hyperlipidemic, diabetic dyslipidemic, and atorvastatin-treated were 5-fold greater than control. Intravascular ultrasound detectable coronary disease and hypertriglyceridemia were only observed in diabetic dyslipidemic and were abolished by atorvastatin. In freshly isolated cells, the Ca²⁺_m response to ET-1 in diabetic dyslipidemic was greater than in control, hyperlipidemic, and atorvastatin-treated groups. Selective ET-1 receptor antagonists showed in the control group that the ET_B subtype inhibits ET_A regulation of Ca²⁺_m. There was almost a complete switch of receptor subtype regulation of Ca²⁺_m from largely ET_A in control to an increased inhibitory interaction between ET_A and ET_B in hyperlipidemic and diabetic dyslipidemic groups, such that neither ET_A nor ET_B antagonist alone could block the ET-1-induced Ca²⁺_m response. The inhibitory interaction was attenuated in the atorvastatin-treated group. In single cells, basal and ET-1-induced tyrosine phosphorylation in diabetic dyslipidemic were more than 3- and 6-fold greater, respectively, than in control, hyperlipidemic, and atorvastatin-treated. Attenuation by atorvastatin of coronary disease and ET-1-induced Ca²⁺_m and tyrosine phosphorylation signaling with no change in cholesterol provides strong evidence for direct actions of atorvastatin and/or triglycerides on the vascular wall.

Address correspondence to: Dr. Michael Sturek, Department of Medical Pharmacology and Physiology, MA415 Medical Sciences Building, School of Medicine, University of Missouri, Columbia, MO 65212. E-mail: sturekm{at}missouri.edu

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