title: Atorvastatin treatment prevents alterations in coronary smooth muscle nuclear Ca2+ signaling in diabetic dyslipidemia.
abstract: Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, alters bulk myoplasmic Ca2+ regulation and inhibits phenotypic modulation and proliferation of vascular smooth muscle in culture. Nuclear Ca2+ (Ca(n)) signaling is tightly coupled to transcriptional events and cell growth. Therefore, we hypothesized that in vivo treatment with atorvastatin would attenuate alterations in mitogen-induced Ca(n) signaling associated with coronary atherosclerosis. Three groups of male Yucatan pigs were treated for 20 weeks: controls, alloxan-induced diabetics fed an atherogenic diet and diabetics fed an atherogenic diet plus atorvastatin (80 mg/day). Right coronary artery single-cell cytosolic Ca2+ (Ca(c)) and Ca(n) responses to the mitogen endothelin-1 (5 x 10(-8) M) were measured by laser confocal microscopy using the calcium indicator Fluo-4. We observed a 39% increase in Ca(c) and a 52% increase in Ca(n) responses to endothelin-1 in cells from diabetic dyslipidemic arteries compared to control. These alterations were prevented in animals treated with atorvastatin. We show that during proliferation, the nucleus of a smooth muscle cell becomes rounded and loses the characteristic multilobular shape, clefts and invaginations. Consistent with this, a redistribution of Ca2+ stores from a transnuclear morphology in controls to a more perinuclear morphology occurred in cells from diabetic dyslipidemic arteries and was prevented by atorvastatin. In addition, the peak Ca(n) responses to endothelin-1 were inversely correlated (r = 0.712) with the extent of the transnuclear distribution of Ca2+ stores and directly correlated (r = 0.874) with the extent of atherosclerosis, as assessed in vivo by intravascular ultrasound. These findings indicate that chronic treatment with atorvastatin directly decreases mitogen-induced Ca(n) mobilization, which we suggest is related to the spatial localization of Ca(n) stores.
authors.affiliation: Department of Physiology, School of Medicine, University of Missouri, Columbia 65212, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Wamhoff
authors.forename: J L
authors.initials: JL
authors.lastname: Dixon
authors.forename: M
authors.initials: M
authors.lastname: Sturek
mesh_terms: D000496:Alloxan / Q000009:adverse effects; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D000069059:Atorvastatin; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine
chemical_list: D000924:Anticholesteremic Agents; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019332:Endothelin-1; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000496:Alloxan; D002784:Cholesterol; D000069059:Atorvastatin; D002118:Calcium