Abstract
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.
MeSH terms
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Actins / metabolism
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Animals
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Antioxidants / pharmacology*
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Coronary Vessels / drug effects*
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Coronary Vessels / metabolism
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Coronary Vessels / physiopathology
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / physiopathology
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Diabetic Cardiomyopathies / etiology
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Diabetic Cardiomyopathies / genetics
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Diabetic Cardiomyopathies / metabolism
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Diabetic Cardiomyopathies / physiopathology
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Diabetic Cardiomyopathies / prevention & control*
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Dinoprostone / analogs & derivatives
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Dinoprostone / metabolism
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Fatty Acids, Monounsaturated / pharmacology*
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Fluvastatin
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Indoles / pharmacology*
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Isoprostanes / metabolism
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Microvessels / drug effects*
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Microvessels / metabolism
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Microvessels / physiopathology
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NADPH Oxidase 2
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Neovascularization, Physiologic / drug effects
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism
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Oxidative Stress / drug effects*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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RNA, Messenger / metabolism
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Rats, Wistar
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Ventricular Function, Left / drug effects
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Ventricular Pressure / drug effects
Substances
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Actins
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Antioxidants
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Fatty Acids, Monounsaturated
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Hif1a protein, rat
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indoles
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Isoprostanes
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Membrane Glycoproteins
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Platelet Endothelial Cell Adhesion Molecule-1
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RNA, Messenger
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Vascular Endothelial Growth Factor A
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smooth muscle actin, rat
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vascular endothelial growth factor A, rat
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Fluvastatin
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Nitric Oxide Synthase Type III
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Nos3 protein, rat
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Cybb protein, rat
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NADPH Oxidase 2
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NADPH Oxidases
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Cyba protein, rat
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Dinoprostone
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8-isoprostaglandin E2