Down‐regulation of OIP5‐AS1 inhibits obesity‐induced myocardial pyroptosis and miR‐22/NLRP3 inflammasome axis

Abstract

AbstractBackgroundObesity can induce myocardial pyroptosis, but the exact mechanism is still unknown. A recent study reported the association of opa‐interacting protein 5‐antisense transcript 1 (OIP5‐AS1), an evolutionarily conserved long noncoding RNA, with pyroptosis. Therefore, this study aimed to investigate the role of OIP5‐AS1 in obesity‐induced myocardial pyroptosis.MethodsOIP5‐AS1 was downregulated in H9c2 cells, followed by treatment with 400 μM palmitic acid (PA). Propidium iodide (PI) staining, lactic dehydrogenase (LDH) release assay, caspase‐1 activity assay, IL‐1β, and IL‐18 activity assay were performed to detect pyroptotic phenotype. The interaction between OIP5‐AS1 and microRNAs (miRNAs) was analyzed using RNA pull‐down and luciferase assay. The effect of OIP5‐AS1 knockdown in high‐fat diet (HFD)‐induced obesity rat on cardiac function, myocardial hypertrophy, fibrosis, and remodeling was evaluated.ResultsFat deposition was observed in cardiomyocytes 24 h after PA treatment; moreover, PA‐treated cardiomyocytes showed significant increase in the rate of pyroptotic cells, release of LDH, protein expressions of NLRP3 and cleaved caspase‐1, and the activity of caspase‐1, IL‐1β, and IL‐18 as well as OIP5‐AS1 expression. These findings suggested that PA activated pyroptosis and induced OIP5‐AS1 expression in cardiomyocytes. Moreover, OIP5‐AS1 knockdown inhibited PA‐induced pyroptosis. Mechanistically, OIP5‐AS1 was found to specifically bind to miR‐22 and to regulate NLRP3 inflammasome‐mediated pyroptosis via miR‐22. Furthermore, OIP5‐AS1 knockdown ameliorated HFD‐induced cardiac dysfunction, myocardial hypertrophy, fibrosis, remodeling, and pyroptosis.ConclusionOur results revealed that downregulation of OIP5‐AS1 can inhibit obesity‐induced myocardial pyroptosis via miR‐22/NLRP3 inflammasome axis. This finding lays a foundation of gene therapy for heart disease targeting OIP5‐AS1.