Abstract
Cardiovascular-disease (CVD)-related mortality has been fueled by the upsurge of non-alcoholic steatohepatitis (NASH). Mesenchymal stem cells (MSCs) were extensively studied for their reparative power in ameliorating different CVDs via direct and paracrine effects. Several reports pointed to the importance of bone marrow mesenchymal stem cells (BM-MSCs) as a reliable therapeutic approach for several CVDs. Nevertheless, their therapeutic potential has not yet been investigated in the cardiotoxic state that is induced by NASH. Thus, this study sought to investigate the molecular mechanisms associated with cardiotoxicity that accompany NASH. Besides, we aimed to comparatively study the therapeutic effects of bone-marrow mesenchymal-stem-cell-derived extracellular vesicles (BM-MSCs-EV) and BM-MSCs in a cardiotoxic model that is induced by NASH in rats. Rats were fed with high-fat diet (HFD) for 12 weeks. At the seventh week, BM-MSCs-EV were given a dose of 120 µg/kg i.v., twice a week for six weeks (12 doses per 6 weeks). Another group was treated with BM-MSCs at a dose of 1 × 106 cell i.v., per rat once every 2 weeks for 6 weeks (3 doses per 6 weeks). BM-MSCs-EV demonstrated superior cardioprotective effects through decreasing serum cardiotoxic markers, cardiac hypoxic state (HIF-1) and cardiac inflammation (NF-κB p65, TNF-α, IL-6). This was accompanied by increased vascular endothelial growth factor (VEGF) and improved cardiac histopathological alterations. Both BM-MSCs-EV and BM-MSCs restored the mitochondrial antioxidant state through the upregulation of UCP2 and MnSOD genes. Besides, mitochondrial Parkin-dependent and -independent mitophagies were regained through the upregulation of (Parkin, PINK1, ULK1, BNIP3L, FUNDC1) and (LC3B). These effects were mediated through the regulation of pAKT, PI3K, Hypoxia, VEGF and NF-κB signaling pathways by an array of secreted microRNAs (miRNAs). Our findings unravel the potential ameliorative effects of BM-MSCs-EV as a comparable new avenue for BM-MSCs for modulating cardiotoxicity that is induced by NASH.
Highlights
Liver manifestations are the key characteristic features of non-alcoholic fatty liver disease (NAFLD), extrahepatic multisystem complications have been widely reported [1,2]
We aimed to investigate the miRNA paradigm of BM-Mesenchymal stem cells (MSCs) that controls phosphatidylinositol 3-kinase (PI3K)/AKT, hypoxic, vascular endothelial growth factor (VEGF) and inflammatory signaling pathways in cardiotoxic state induced by non-alcoholic steatohepatitis (NASH)
This was achieved through studying the miRNA paradigm of bone marrow mesenchymal stem cells (BM-MSCs) that controls PI3K/AKT, hypoxic, VEGF and inflammatory signaling pathways in cardiotoxic state induced by NASH
Summary
Liver manifestations are the key characteristic features of non-alcoholic fatty liver disease (NAFLD), extrahepatic multisystem complications have been widely reported [1,2]. NAFLD results from metabolic derangements due to surplus lipid overloads affecting hepatic structure and function. It eventually progresses into non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Increased prevalence of coronary artery disease and structural myocardial alterations was reported in NAFLD/NASH [4], suggesting that these associated CVDs may be independent of the presence of traditional cardiovascular (CV) risk factors [4–6]. CV events are reported with early stages of NASH, being a primarily mitochondrial disease that affects the overall ATP balance and energy state [10]
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