The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

Abstract

Aims/hypothesis We evaluated the anti-atherosclerotic effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, rosuvastatin, and the angiotensin II receptor blocker (ARB), candesartan, alone and in combination, in the streptozotocin-induced diabetic apolipoprotein Edeficient (Apoe −/− ) mouse. Methods Control and streptozotocin-induced diabetic Apoe −/− mice received rosuvastatin (5 mg kg −1 day −1 ), candesartan (2.5 mg kg −1 day −1 ), dual therapy or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent visual quantification. The abundance of proteins was measured using immunohistochemistry. Results Diabetes was associated with a fourfold increase in total plaque area. Rosuvastatin attenuated plaque area in diabetic mice in the absence of lipid-lowering effects. The anti-atherosclerotic effect of rosuvastatin was comparable to that observed with candesartan. A similar beneficial effect was seen with dual therapy, although it was not superior to monotherapy. Rosuvastatin treatment was associated with attenuated accumulation of AGE and AGE receptor (RAGE) in plaques. Similar beneficial effects on markers of oxidative stress were seen with the ARB and statin. Candesartan was more effective at reducing macrophage accumulation and collagen I abundance in plaques compared with rosuvastatin. The combined effect of candesartan and rosuvastatin was superior in reducing macrophage infiltration, monocyte chemoattractant protein-1 level, vascular AGE accumulation and RAGE abundance in the vascular wall. Furthermore, the combination tended to be more effective in reducing smooth muscle cell infiltration and connective tissue growth factor abundance in plaques. Conclusions/interpretation Rosuvastatin has direct antiatherosclerotic effects in diabetic macrovascular disease. These effects are independent of effects on lipids and comparable to the effects observed with candesartan.

Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease

“…Certain antihypertensive and lipid-lowering drugs may affect AGEs metabolism. 19,20 However, (multivariate) linear regression analysis of SAF does not suggest such an effect in our cohort. Stratification of the results of the Cox regression analyses by the use of these drugs would have been interesting.…”

Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients

“…Yoshida et al [26] suggested that telmisartan, an angiotensin II type I receptor blocker, acts as an anti-inflammatory agent against AGE by suppressing RAGE expression via pepoxisome proliferator-activated receptor-gamma activation. Statins and the angiotensin II type I receptor blocker were reported to attenuate atherosclerosis via their effects on advanced glycation, oxidative stress, and inflammation in an animal model [27]. Acute modulation by these cardiovascular agents in patients with acute stroke has not been clarified.…”

Effects of HMG-CoA Reductase Inhibitor on Experimental Autoimmune Myocarditis

“…Mice successfully induced with EAM (n030) were divided into three groups: non-treated EAM group (group N, n010); low-dose rosuvastatin group (1 mg/kg/day, group L, n010), and high-dose rosuvastatin group (10 mg/kg/day, group H, n010). The rosuvastatin dosages were determined from reports of previous work [9,10]. Rosuvastatin therapy started at the same time of immunization.…”