Effects of Pravastatin on Type 1 Diabetic Rat Heart with or without Blood Glycemic Control

Abstract

Although statins have been suggested to attenuate the progression of diabetic cardiomyopathy, its effect without glycemic control remains unclear. Therefore, we evaluated the effect of pravastatin on diabetic rat hearts according to glycemic control. Rats were randomly divided into five groups: control (C), diabetes (D), diabetes with insulin (I), diabetes with pravastatin (P), and diabetes with insulin and pravastatin (IP). Eight weeks after allocated treatments, the heart was extracted and analyzed following echocardiography. Cardiac fibrosis was measured using Masson's trichrome stain. Cardiac expression of collagen I/III, matrix metalloproteinase (MMP)-2, MMP-9, and angiotensin-converting enzyme (ACE)/ACE2 was evaluated by immunohistochemistry and/or Western blot. Enzyme-linked immunosorbent assay was used for measuring reactive oxygen species (ROS). Diabetic groups without glycemic control (D and P) showed significantly impaired diastolic function and increased levels of cardiac fibrosis, collagen I/III, MMP-2, MMP-9, and ROS production. However, there were little significant differences in the outcomes among the control and two glucose-controlled diabetic groups (I and IP). Groups C and IP showed more preserved ACE2 and lower ACE expressions than the other groups did (D, I, and P). Our study suggested glycemic control would be more important to attenuate the progression of diabetic cardiomyopathy than pravastatin medication.

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“…In a model of experimental atherosclerosis in rabbits, atorvastatin increased ACE2 protein levels in heart and kidneys, compared to untreated atherosclerotic animals (Dong et al, 2008; South et al, 2020). Similar results were observed using rosuvastatin or pravastatin in rat vascular balloon injury or diabetes (Li et al, 2013; Min et al, 2018). However, in those studies, ACE2 levels were decreased in injured tissues compared to healthy groups, and therefore, ACE2 up‐regulation induced by statins is only described under disease situations.…”

Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2

“…Fluvastatin reduces diabetic cardiac fibrosis, improves cardiac function and enhances ACE2 expression in glucose-controlled diabetic rats (Shin et al, 2017). Similar findings with cardiac ACE2 preservation have been observed for pravastatin (Min et al, 2018). Likewise, atorvastatin inhibits TNF-α mediated suppression of ACE2 and upregulation of ACE in cultured vascular smooth muscle cells.…”

Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients

“…These effects were attributed to the recovered ratio of ACE/ACE2 rather than an increased level of ACE2 [ 78 ]. Further studies in diabetic rats confirmed that statin administration increased ACE2 mRNA in cardiac tissue from insulin-controlled groups, although this was not accompanied by significant effects on cardiac fibrosis and reactive oxygen species generation [ 79 , 80 ]. In our current report, 33% of COVID19 cases that used statins were diabetic.…”