Exercise Training Restores the Cardiac Microrna-16 Levels Preventing Microvascular Rarefaction in Obese Zucker Rats

Abstract

Objective: To evaluate the effects of aerobic exercise training (AET) on cardiac miRNA-16 levels and its target gene VEGF related to microvascular rarefaction in obese Zucker rats (OZR). Methods: OZR (n = 11) and lean (L; n = 10) male rats were assigned into 4 groups: OZR, trained OZR (OZRT), L and trained L (LT). Swimming exercise training lasted 60 min, 1×/day/10 weeks, with 4% body weight workload. Cardiac angiogenesis was assessed by histological analysis (periodic acid-Schiff) by calculating the capillary/fiber ratio. The protein expressions of VEGF, VEGFR2, and CD31 were evaluated by western blot. The expression of miRNA-16 was evaluated by real-time PCR. Results: Heart rate decreased in the trained groups compared to sedentary groups. The cardiac capillary/fiber ratio was reduced in OZR compared to L, LT and OZRT groups, indicating that aerobic exercise training (AET) was capable of reversing the microvascular rarefaction in the obese animals. miRNA-16 expression was increased in OZR compared to L, LT and OZRT. In contrast, its target, VEGF protein expression was 24% lower in OZR compared to L group, which has been normalized in OZRT group. VEGFR2 protein expression was increased in trained groups compared to their controls. CD31, a endothelial cells marker, showed increased expression in OZRT compared to OZR, indicating greater vascularization in OZRT group. Conclusion: AET induced cardiac angiogenesis in obese animals. This revascularization is associated with a decrease in miRNA-16 expression permissive for increased VEGF protein expression, suggesting a mechanism for potential therapeutic application in vascular diseases.

Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

“…Increased miRNA-16 expression was associated with the progression of capillary rarefaction in the hearts of the obese Zucker rats. Conversely, swimming exercise restored the levels of miRNA-16 and prevented capillary rarefaction [ 110 ]. The study in hypertension rat models by Fernandes et al indicates the relevance of miRNA-16, -21 and -126 induced by ET in reducing blood pressure and preventing capillary rarefaction [ 111 ].…”

A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia: Implications of Physical Activity to Tumor Regression

“…In conclusion, many studies show that both aerobic and resistance physical exercise control the expression of miRs that are dysregulated by diseases as hypertension, diabetes, and obesity [68,69,104,105]. Physical exercise rebalances the expression of the miRs involved with those alterations reverses structural deleterious changes in the skeletal muscle and restores tissue or prevents deterioration [66].…”

“…Several studies also demonstrate that aerobic physical activity normalizes the expression of aberrant miRs due to diseases such as myocardial infarction, hypertension, diabetes, and obesity. That these pathologies induce molecular and structural alterations and aerobic physical exercise is a beneficial stimulus for the reversal and control of these deleterious alterations such as muscle mass decrease and microvascular rarefaction [66][67][68][69].…”

Physical Exercise Protects Against Endothelial Dysfunction in Cardiovascular and Metabolic Diseases

“…miRNA-16 has been reported to inhibit endothelial function and angiogenesis both in vitro and in vivo by targeting vascular endothelial growth factor receptor-2 (VEGFR2) and fibroblast growth factor receptor-1 (FGFR1) [117]. Recently, miRNA-16 was found to be significantly downregulated by aerobic exercise training in obese animals and was associated with increased VEGF expression and revascularization [118]. miR-492 has been found to be upregulated by swimming in aortic endothelium and to restore endothelial function and delay the progression of atherosclerosis by diminishing the level of resistin in aortic endothelium [119].…”