Mir-210-3p enhances cardiomyocyte apoptosis and mitochondrial dysfunction by targeting the ndufa4 gene in sepsis-induced myocardial dysfunction

Abstract

Sepsis-induced myocardial dysfunction (SIMD) is a common complication with high incidence rates in sepsis patients. This study aimed to investigate the roles of miR-210-3p in regulating cardiomyocyte apoptosis and mitochondrial dysfunction associated with SIMD pathogenesis. A rat sepsis model was established by cecal ligation and puncture. Serum inflammatory factors, myocardial tissue apoptosis, and expression of miR-210-3p were evaluated. In vitro, miR-210-3p expression in H9C2 cells was altered by transfection with its mimics or inhibitors. H9C2 viability was assessed via CCK-8 assay, and reactive oxygen species (ROS) production and apoptosis were detected through flow cytometry. The targeting regulatory relations between miR-210-3p and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4) were validated by dual luciferase reporter assay. The rat sepsis model showed increased serum TNF-α and IL-6 levels, significant myocardial tissue injuries and apoptosis with decreased Bcl-2 and increased Caspase-1 protein levels. In vitro, septic rat serum suppressed viability, promoted ROS production and apoptosis, impaired COX IV activities and increased cytochrome re-lease in H9C2 cells. The expression of miR-210-3p was greatly increased in myocardial tissues of septic rats and septic serum-treated H9C2 cells. miR-210-3p directly binds to the 3’ UTR of the NDUFA4 gene. Septic rat serum suppressed NDUFA4 and Iron-Sulfur Cluster Assembly Protein U gene expressions in H9C2 cells. The above cellular and molecular alterations in H9C2 cells induced by septic serum were enhanced by miR-210-3p mimics and abrogated by miR-210-3p inhibitors. miR-210-3p promoted SIMD pathogenesis by targeting NDUFA4 to enhance cardiomyocyte apoptosis and impair mitochondrial function.