Apelin deficiency exacerbates cardiac injury following infarction by accelerating cardiomyocyte ferroptosis.

Abstract

Apelin is an endogenous ligand for the Apelin receptor and is a critical protective effector in myocardial infarction (MI). Nevertheless, these protective mechanisms are not fully understood. Ferroptosis is the major driving factor of MI. This study aimed to investigate the effects and underlying regulatory mechanisms of Apelin on cardiomyocyte ferroptosis in MI. A model of MI was induced in adult C57BL/6J wild type (WT) and Apelin knockout (Apelin^-/-) mice. Cardiac function was examined by echocardiography 4 weeks post-MI. RNA-seq, histochemical analyses, and Western blotting were applied to examine the effects of Apelin knockout on the transcriptome and pathological remodeling following infarction and the molecular mechanisms. Mice neonatal cardiomyocytes (NCMs) were used to establish the serum deprivation/hypoxia (SD/H) model in vitro. Compared with WT mice, Apelin^-/- mice exhibited more severe impairment of cardiac function and increased fibrosis following infarction. Transcriptome and biochemical analyses revealed the involvement of ferroptosis in mediating Apelin function in MI. Ferroptosis-related proteins were significantly increased post-MI in Apelin^-/- mice whereas p-AMPK was greatly decreased. Apelin treatment activated the AMPK pathway and thereby inhibited ferroptosis of NCMs induced by SD/H in vitro. These protective effects were partially reversed by AMPK inhibitor. Apelin deficiency aggravated cardiac dysfunction following infarction by activating cardiomyocyte ferroptosis via inhibition of the AMPK pathway. This offers a novel potential therapeutic target for MI treatment.