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Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature

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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 p22phox and gp91phox mRNA expression, and myocardial 8-iso-prostaglandin F2α (PGF2α) 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 × 103 mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22phox and gp91phox mRNA expression and myocardial PGF2α 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.

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Authors and Affiliations

  1. Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Takuya Shida, Takashi Nozawa, Mitsuo Sobajima, Hiroyuki Ihori, Akira Matsuki & Hiroshi Inoue

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  1. Takuya Shida
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  2. Takashi Nozawa
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  3. Mitsuo Sobajima
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Correspondence to Takashi Nozawa.

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Shida, T., Nozawa, T., Sobajima, M. et al. Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessels 29, 532–541 (2014). https://doi.org/10.1007/s00380-013-0402-6

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