IGF2BP2通过m6A修饰MAP2K1促进脓毒症诱导心肌损伤中的心肌细胞铜死亡

Abstract

IGF2BP2 promotes cardiomyocyte cuproptosis in sepsis-induced myocardial injury. • IGF2BP2 stabilizes MAP2K1 mRNA through m 6 A methylation modification. • Knockdown of IGF2BP2 inhibits cardiomyocyte cuproptosis by downregulating MAP2K1. Background Sepsis-induced myocardial injury (SIMI) has become an important cause of death in septic patients, and it is a multi-faceted pathophysiological process. The present study aims to understand how insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) regulates cardiomyocyte cuproptosis through an m 6 A-dependent regulation of mitogen-activated protein kinase kinase 1 (MAP2K1), and advance our knowledge of SIMI. Methods In vivo and in vitro SIMI models were developed through lipopolysaccharide (LPS) administration in mice and AC16 cardiomyocytes, respectively. The functions of IGF2BP2 and MAP2K1 in regulating cuproptosis under septic myocardial injury were explored through loss- and gain-of-function approaches. Furthermore, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) experiments as well as actinomycin D experiments confirmed the regulatory interaction of IGF2BP2 with MAP2K1. Results In SIMI models, the IGF2BP2 mRNA and protein expressions were all significantly upregulated, accompanied by myocardial pathological damage and poor cardiac function. Knockdown of IGF2BP2 considerably lessened LPS-induced myocardial injury, lowered copper levels in serum and myocardial tissue, and rectified the changed expression of key cuproptosis-related proteins such as MAP2K1, solute carrier family 31 member 1 (SLC31A1), ferredoxin 1 (FDX1), heat shock protein 70 (HSP70), dihydrolipoamide S -acetyltransferase (DLAT), and lipoyl synthase (LIAS). Mechanistically, IGF2BP2 interacts with MAP2K1 mRNA to improve the mRNA stability and protein expression of MAP2K1 through N6-Methyladenosine (m 6 A) modification. In addition, overexpression of MAP2K1 abrogated the suppressive effects of IGF2BP2 knockdown on ca