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The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts

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Abstract

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.

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Acknowledgements

This study was supported by Faculty Research Fund, Sunkyunkwan University, 2011 (S-2011-1338-000). Novartis Pharma AG (Basel) Switzerland donated the fluvastatin used in this study. The authors have no commercial, proprietary, or financial interest in the products or companies described in this article except for the above-mentioned donation.

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    1. Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 06351, Korea

      Young Hee Shin, Jeong Jin Min, Jong-Hwan Lee, Eun-Hee Kim, Go Eun Kim, Myung Hee Kim, Jeong Jin Lee & Hyun Joo Ahn

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    Y. H. Shin and J. J. Min contributed equally as the co-first author of this manuscript.

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    Shin, Y.H., Min, J.J., Lee, JH. et al. The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts. Heart Vessels 32, 618–627 (2017). https://doi.org/10.1007/s00380-016-0936-5

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