Resveratrol Treatment Reduces Cardiac Progenitor Cell Dysfunction and Prevents Morpho-Functional Ventricular Remodeling in Type-1 Diabetic Rats

Abstract

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n = 128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n = 54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n = 64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic “milieu” on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

“…In another study, resveratrol treatment has been shown to normalize free fatty acid oxidation, enhance glucose utilization, and reduce biomarkers of oxidative stress in the hearts of streptozocin-induced diabetic rats [242]. Similarly, resveratrol treatment was found to improve the cardiac function in streptozocin-induced type 1 diabetic rats, at least in part, through preserving the functional abilities of cardiac stem/progenitor cells [249]. Moreover, in streptozocin-induced diabetic mice, both low (60 mg/kg/day) and high (300 mg/kg/day) dose resveratrol treatment improved cardiac function, ameliorated oxidative injury, and reduced apoptosis in the hearts of treated diabetic mice [250].…”

Calcium signaling in diabetic cardiomyocytes

“…T1D contractile dysfunction is characterized by a decrease in fractional shortening [17,18], ejection fraction [19], and heart rate [20]. However, unlike other heart failure models, they do not always develop cardiac hypertrophy [20,21], heart weight change [18,22] or cardiac atrophy [23]. This particularity is possibly due to apoptosis [24] and/or depression of cardiomyocyte volume [25].…”

Chronic resveratrol administration improves diabetic cardiomyopathy in part by reducing oxidative stress

“…Apart from that, Zhang et al [9] have shown that treatment with resveratrol (20 mg/kg/day orally for 4 weeks) improves left ventricular (LV) diastolic relaxation by inhibiting oxidative/nitrosative stress. A very recent study has shown that 8 weeks treatment with resveratrol (2.5 mg/kg/day; IP) improves diabetic heart function through reducing ventricular inflammation and remodeling [10]. In another recent study it has been shown that resveratrol given at 2.5 mg/ /kg/day orally for 4 weeks prevented from cardiac and vascular dysfunction in diabetic rats through its effect on redox balance [5].…”