Resveratrol and Adipose-derived Mesenchymal Stem Cells Are Effective in the Prevention and Treatment of Doxorubicin Cardiotoxicity in Rats

Abstract

Anthracyclines can cause severe cardiac toxicity leading to heart failure. The aim of this study was to determine the effects of cardioprotective polyphenolic compound resveratrol (RES) and adipose-derived mesenchymal stem cells (ADMSCs) on cardiac tissue of rats treated with doxorubicin (DOX). Forty-two female and three male Wistar-Albino rats were included in the study. The study groups and the control groups were as follows: Group I: DOX; Group II: DOX + RES; Group III: DOX + ADMSCs; Group IV: DOX + RES + ADMSCs; Group V: Sham operation; and Group VI: normal saline. ADMSCs obtained from male rats were defined with stem cell markers [CD11b/c(-), CD45(-), CD90(+), CD44(+), and CD49(+)]. DOX 12 mg/kg intraperitoneally (i.p.) was injected as a single dose in female rats. Resveratrol 100 mg/kg was injected three times i.p. in Groups II and IV. ADMSCs 2 × 10(6) cells/kg/dose were labeled with bromodeoxyuridine (BrdU) and injected i.p. for a total of three times in Groups III and IV. When the study was terminated after 4 weeks, the beating hearts were connected to a Langendorff setup and records were obtained for 30 minutes. Histopathological, immunhistochemical, and immunofluorescent examination with H&E, Troponin I, and BrdU stains were also performed. Also, ADMSCs were demonstrated in the myocardium of transplanted rats. Left ventricle functions and myocardial histology demonstrated significant impairment in DOX only group compared to groups with ADMSCs (P < .05). We suggest that RES and ADMSCs were successful in the prevention and treatment of the doxorubicin cardiomyopathy in rats. The hypothetical mechanisms of regeneration are multiple, including cell differentiation and autocrine/paracrine effects of ADMSCs.

Functional and Structural Assessment of the Effect of Human Umbilical Cord Blood Mesenchymal Stem Cells in Doxorubicin‐Induced Cardiotoxicity

“…The MSCs-treated group showed a significant increase of MVP, EDP, dP/dt max, and dP/dt min at the end of the 6th week; consistent with previous studies [Rota et al, 2007;Ammar et al, 2015]. General improvement of the left ventricular function after systemic administration of MSCs was also shown by Oliveira et al [2013] and Pinarli et al [2013]. MSCs-mediated cardiac repair and function saving effects include modulation of inflammation, promotion of angiogenesis and reducing cardiac fibrosis that is critical in improving the performance and the function of the affected heart [Loffredo et al, 2011].…”

“…These findings are consistent with previous studies [Di et al, 2012;Mohammadi Gorji et al, 2012;Oliveira et al, 2013;Ammar et al, 2015], reflecting the beneficial effects of MSCs on DOX-induced cardiotoxicity and heart failure. Moreover, MSCstreated group, showed improved survival as reported by Di et al [2012] and Pinarli et al [2013]. This could be attributed to the capacity of MSCs to act as a trophic factor pool combating different degenerating and debilitating conditions [Wei et al, 2013].…”

5‐Azacytydine and resveratrol reverse senescence and ageing of adipose stem cells via modulation of mitochondrial dynamics and autophagy

“…Our results are consistent with the recent findings of Latorre et al who discovered that treatment with resveralogues reversed cellular senescence in human primary fibroblasts. Many other studies confirmed the beneficial effects of RES on MSC biology, mainly by enhancing their differentiation potential …”

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy‐induced toxicity

“…Anthracycline‐induced cardiotoxicity is attributed mainly to free radical formation in the mitochondria resulting in apoptosis of cardiac cells; MSCs were able to improve histopathologic and functional features and result in improved cardiac function after doxorubicin treatment in animal models . Additionally, bmMSCs were shown to regenerate doxorubicin‐induced nephropathy by reducing glomerular inflammation and preserving podocyte viability .…”