Abstract
Endothelial progenitor cells (EPCs) improve endothelial impairment, which in turn restores endothelial function in patients with heart failure (HF). In the present study, we tested whether fenofibrate, with its anti-inflammatory and vasoprotective effects, could improve myocardial function by activating EPCs through the eNOS pathway in a doxorubicin (DOX)-induced cardiomyopathy mouse model. Wild-type mice were divided into 4 groups and treated with vehicle, DOX + saline, DOX + fenofibrate, and DOX + fenofibrate + L-NAME (N(ω)-nitro-L-arginine methyl ester). DOX-induced cardiac atrophy, myocardial dysfunction, the number of circulating EPCs and tissue inflammation were analyzed. Mice in the DOX + fenofibrate group had more circulating EPCs than those in the DOX + saline group (2% versus 0.5% of total events, respectively) after 4 weeks of treatment with fenofibrate. In addition, the inhibition of eNOS by L-NAME in vivo further abolished the fenofibrate-induced suppression of DOX-induced cardiotoxic effects. Protein assays revealed that, after DOX treatment, the differential expression of MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), and NT-pro-BNP (N-terminal pro-B-type natriuretic peptide) between saline- and DOX-treated mice was involved in the progression of HF. Mechanistically, fenofibrate promotes Akt/eNOS and VEGF (vascular endothelial growth factor), which results in the activation of EPC pathways, thereby ameliorating DOX-induced cardiac toxicity.
Highlights
Endothelial progenitor cells (EPCs) improve endothelial impairment, which in turn restores endothelial function in patients with heart failure (HF)
To clarify whether suppressed EPC numbers were associated with DOX-induced cardiac dysfunction, circulating EPC numbers were evaluated by flow cytometry after 2 weeks of DOX injection
There was a significant correlation between the number of circulating EPCs and left ventricular short axis fractional shortening (LVFS) (r = 0.59, P = 0.0002, Fig. 2C), whereas there was significant correlation with left ventricular ejection fraction (LVEF) measurements (r = 0.4012, P = 0.0169 Fig. 2D).These findings indicated that treatment with fenofibrate ameliorated DOX-induced cardiac dysfunction and that decreased numbers of circulating EPCs may be involved in DOX-induced cardiac dysfunction
Summary
Endothelial progenitor cells (EPCs) improve endothelial impairment, which in turn restores endothelial function in patients with heart failure (HF). We tested whether fenofibrate, with its anti-inflammatory and vasoprotective effects, could improve myocardial function by activating EPCs through the eNOS pathway in a doxorubicin (DOX)-induced cardiomyopathy mouse model. Fenofibrate promotes Akt/eNOS and VEGF (vascular endothelial growth factor), which results in the activation of EPC pathways, thereby ameliorating DOX-induced cardiac toxicity. Fenofibrate exerted a protective effect against vascular dysfunction by its anti-inflammatory properties, we observed that fenofibrate, a PPARα agonist, stimulated angiogenesis by improving endothelial precursor cell function, mobilization, and homing of endothelial progenitor c ells[21,22]. We aimed to investigate whether fenofibrate could have a protective effect against DOX-associated myocardial damage and to clarify the role of EPCs in DOX-induced heart toxicity in vivo and in vitro
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