Nitro-oleic acid alleviates inflammation and fibrosis by regulating macrophage polarization and fibroblast activation to improve cardiac function in MI mice.

Chronic heart failure, caused by myocardial fibrosis after acute myocardial infarction (AMI), remains a serious clinical problem that needs urgent resolution. Nitro-oleic acid (OA-NO2), an electrophilic nitro-fatty acid found in human plasma, is believed to regulate various pathophysiological functions, particularly anti-inflammation and anti-fibrosis. However, the role of OA-NO2 in AMI remains unexplored. Thus, our aim was to investigate whether OA-NO2 could ameliorate post-myocardial infarction fibrosis, improve cardiac function, and elucidate its mechanism in AMI mice. In vivo experiments involved constructing an AMI mice model and administering OA-NO2 via subcutaneous osmotic minipumps. Echocardiography and transmission electron microscope experiments indicated that OA-NO2 can alleviate myocardial injury and improve heart systolic function. Transcriptomics of cardiac tissue suggested that OA-NO2 improved myocardial fibrosis. Immunohistochemistry and qPCR results demonstrated OA-NO2's reduction in the accumulation of extracellular matrix (Collagen I and Collagen III). In vitro experiments showed that OA-NO2 remarkably suppressed the activation of cardiac fibroblasts to myofibroblast transition induced by transforming growth factor-β (TGF-β). Furthermore, OA-NO2 inhibited the expression of α-SMA, collagen I, and collagen III via the TGF-β/smad2/3 signaling pathway. Immunofluorescence experiments and ELISA detection revealed that OA-NO2 not only alleviated myocardial fibrosis but also reduced myocardial inflammation and decreased inflammatory factors (TNF-α, IL-1β, IL-6, and MCP-1). Mechanistically, OA-NO2 significantly reduced the polarization of LPS-induced macrophages into M1-type macrophages by inhibiting the NF-κB (P65) related pathways. Therefore, OA-NO2 could ameliorate postmyocardial infarction fibrosis and improve cardiac function by inhibiting the activation of cardiac myofibroblasts and M1 macrophages.