Simvastatin Improves Diabetes-Induced Coronary Endothelial Dysfunction

Abstract

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors decrease cardiovascular morbidity in diabetic patients, but the mechanism is unclear. We studied the actions of simvastatin (SIM) in enhancing NO bioavailability and reducing oxidative stress in coronary vessels from diabetic rats and in rat coronary artery endothelial cells (RCAEC) exposed to high glucose. Coronary arteries isolated from diabetic rats showed decreases in acetylcholine (ACh)-mediated maximal relaxation from 81.0 Ϯ 4.5% in controls to 43.5 Ϯ 7.6% at 4 weeks and 22.3 Ϯ 0.6% at 10 weeks of diabetes. This effect was associated with oxidative stress in coronary vessels as shown by dichlorofluorescein (DCF) imaging and nitrotyrosine labeling. Diabetes also reduced trans-coronary uptake of [ 3 H]L-arginine. Supplemental L-arginine (50 mg/kg/day p.o.) did not improve coronary vasorelaxation to ACh. However, SIM treatment (5 mg/kg/day subcutaneously) improved maximal ACh relaxation to 65.8 Ϯ 5.1% at 4 weeks and 47.1 Ϯ 3.9% at 10 weeks. Coronary arteries from rats treated with both SIM and L-arginine demonstrated the same maximal relaxation to ACh (66.1 Ϯ 3%) as SIM alone. Mevalonate and L-NAME (N -nitro-L-arginine methyl ester hydrochloride) inhibited the response to ACh in SIM-treated diabetic rats. Coronary arteries from all groups relaxed similarly to sodium nitroprusside. SIM increased endothelial NO synthase protein levels and blocked diabetes-induced increases in DCF and nitrotyrosine labeling in diabetic coronary vessels. SIM treatment restored normal NO levels in media from high-glucosetreated RCAEC and plasma of diabetic rat. Treatment with SIM or the NADPH oxidase inhibitor apocynin also blocked high-glucoseinduced increases in reactive oxygen species and superoxide formation in RCAEC. Taken together, these data suggest that SIM improves diabetes-induced coronary dysfunction by reducing oxidative stress and increasing NO bioavailability.

Influence of fluvastatin on cardiac function and baroreflex sensitivity in diabetic rats

“…According to recent reports, statins, including fluvastatin, exert a positive influence on the cardiovascular system not only by regulating blood lipids but also in a cholesterol-independent manner [34,35] . Tawfik et al demonstrated that simvastatin, a drug similar to fluvastatin, prevented impaired coronary endothelial cell-dependent vasorelaxation in 4-week STZ-induced diabetic rats [36] . Moreover, statins up-regulated neuronal nitric oxide synthase (nNOS) expression in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, down-regulated sympathetic nerve activity and achieved an improvement in the BRS [37] .…”

Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

“…These mechanisms might participate in the improvement of endothelial dysfunction observed with statins in different cardiovascular pathologies. 22,39,40 Atorvastatin downregulated the increase in collagen content and improved the alterations of elastin structure induced by Ang II in MRA. More importantly, these effects had a physiological consequence.…”

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

“…Although the results of the two drugs were in parallel, the neuro and vascular protective effects of atorvastatin were usually superior to those of FeTPPs, but did not reach significance, a fact possibly attributable to the pleiotropic effects of statins, including antioxidant effects and inhibition of GTP-binding proteins, in addition to their known cholesterol-lowering ability [13,17,[45][46][47][48]. While previous studies examined the protective effects of statins in retinas from ischaemia/reperfusion models or in other tissue from diabetic animals, our study is the first to demonstrate the neuroprotective effects of atorvastatin in the diabetic retina.…”