Adipose-derived mesenchymal stem cells attenuate doxorubicin-induced cardiomyopathy in rats: association with miR-146a/NF-κB/TLR-4 transcriptional modulation

Abstract

Abstract Background Doxorubicin (DOX) is an effective chemotherapeutic drug, but its clinical use is limited by dose-dependent cardiotoxicity and cardiomyopathy. Adipose-derived mesenchymal stem cells (ADMSCs) may offer cardioprotective effects through regenerative, antioxidant, and immunomodulatory mechanisms. This study investigated the therapeutic potential of ADMSCs in DOX-induced cardiomyopathy in rats, with focus on miR-146a expression and transcriptional modulation of the NF-κB/TLR-4 inflammatory signaling axis. NF-κB was selected because it plays a central role in regulating inflammatory signaling and is well established as a key link between oxidative stress and myocardial injury in doxorubicin-induced cardiotoxicity, compared with other downstream apoptotic pathways. Methodology Forty male rats were assigned to control and DOX-treated groups. Cardiomyopathy was induced by intraperitoneal DOX injection at 2.5 mg/kg every other day for 14 days, for a total of seven injections and a cumulative dose of 17.5 mg/kg. During the therapeutic phase, ADMSCs were administered intravenously. Serum creatine kinase activity, cardiac oxidative stress markers, miR-146a, NF-κB, and TLR-4 expression were assessed. Alkaline and neutral comet assays, histopathological examination, and ADMSC homing evaluation were also performed. Results DOX administration increased serum creatine kinase activity and malondialdehyde levels, reduced catalase activity, and induced cardiac DNA damage and histopathological alterations. Molecular analysis showed a slight, non-significant downward trend in miR-146a expression during induction, together with significant upregulation of NF-κB and TLR-4 expression. ADMSC treatment ameliorated several DOX-associated biochemical, molecular, genotoxic, and histopathological alterations. However, some physiological parameters showed only partial or non-significant improvement. Conclusion These findings suggest that ADMSCs may attenuate DOX-induced cardiomyopathy, at least partly, through reduced oxidative stress and DNA damage, improved myocardial histology, and transcriptional modulation of the miR-146a/NF-κB/TLR-4 axis.