(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Diabetic-Cardiomyopathies

Independently of the lipid-lowering effects, statin has been reported to attenuate the development of diabetic cardiomyopathy. However, the effect of statin in glucose-controlled diabetic condition has not been demonstrated. We evaluated the effect of fluvastatin on cardiac function, fibrosis, and angiotensin-converting enzyme-2 (ACE2) expression in glucose-controlled diabetic rats. Male Wistar rats were randomly divided into four groups: control (Group C), diabetes (Group D), diabetes with insulin (Group I), and diabetes with insulin and fluvastatin (Group I+F). Diabetes was induced by a single injection of streptozotocin (65 mg/kg). After 8 weeks, the hearts were extracted following echocardiographic evaluation. Cardiac fibrosis was analyzed using Masson's trichrome stain. Collagens I and III and ACE2 expressions were evaluated by immunohistochemistry and western blot. Group D showed reduced cardiac systolic function compared to the other groups (all P < 0.05). However, diastolic function estimated by E/A ratio was significantly decreased in groups D and I (median: 0.88 and 1.45, respectively) compared to groups C and I+F (2.97 and 2.15) (all P < 0.05). Cardiac fibrosis was more severe in groups D and I than in groups C and I+F (all P < 0.05) on Masson's trichrome stain. On immunohistochemistry, ACE2 expression was significantly decreased only in group D (all P < 0.05). However, collagen I and III showed higher expressions in group D compared to groups C and I+F while no significant difference was observed compared with group I (all P < 0.05). On western blot, collagen I and ACE2 expressions in group D (median: 1.78 and 0.35, respectively) were significantly different from groups C (references: 1) and I+F (0.76 and 1.21) (all P < 0.05), but not from group I (1.19 and 0.92). Our study suggested a combination of fluvastatin and insulin would be more effective than insulin alone in diabetic hearts. However, the exact mechanism remains to be elucidated.

Topics: Animals; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Echocardiography; Endothelin-Converting Enzymes; Fatty Acids, Monounsaturated; Fibrosis; Fluvastatin; Glucose; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Indoles; Male; Myocardium; Rats; Rats, Inbred Lew

Diabetic cardiomyopathy is associated with increased oxidative stress and vascular endothelial dysfunction, which lead to coronary microangiopathy. We tested whether statin-induced redox imbalance improvements could ameliorate diabetic cardiomyopathy and improve coronary microvasculature in streptozotocin-induced diabetes mellitus (DM). Fluvastatin (10 mg/kg/day) or vehicle was orally administered for 12 weeks to rats with or without DM. Myocardial oxidative stress was assessed by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase subunit p22(phox) and gp91(phox) mRNA expression, and myocardial 8-iso-prostaglandin F(2α) (PGF(2α)) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-α-smooth muscle actin (SMA) antibodies. Fluvastatin did not affect blood pressure or plasma cholesterol, but attenuated increased left ventricular (LV) minimum pressure and ameliorated LV systolic dysfunction in DM rats in comparison with vehicle (LV dP/dt, 8.9 ± 1.8 vs 5.4 ± 1.0 × 10(3) mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22(phox) and gp91(phox) mRNA expression and myocardial PGF(2α) levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1α mRNA expression. CD31-positive cell densities were lower in DM rats than in non-DM rats (28.4 ± 13.2 vs 48.6 ± 4.3/field, P < 0.05) and fluvastatin restored the number (57.8 ± 18.3/field), although there were no significant differences in SMA-positive cell densities between groups. Fluvastatin did not affect cardiac function, oxidative stress, or vessel densities in non-DM rats. These results suggest that beneficial effects of fluvastatin on diabetic cardiomyopathy might result, at least in part, from improving coronary microvasculature through reduction in myocardial oxidative stress and upregulation of angiogenic factor.

Topics: Actins; Animals; Antioxidants; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dinoprostone; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Isoprostanes; Male; Membrane Glycoproteins; Microvessels; NADPH Oxidase 2; NADPH Oxidases; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Oxidative Stress; Platelet Endothelial Cell Adhesion Molecule-1; Rats, Wistar; RNA, Messenger; Vascular Endothelial Growth Factor A; Ventricular Function, Left; Ventricular Pressure