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+ (Can) 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 Can 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+ (Cac) and Can responses to the mitogen endothelin-1 (5 × 10-8M) were measured by laser confocal microscopy using the calcium indicator Fluo-4. We observed a 39% increase in Cac and a 52% increase in Can 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 Can 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 Can mobilization, which we suggest is related to the spatial localization of Can stores.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- Confocal microscopy
- Electron microscopy
- Intravascular ultrasound