Adrenomedullin 2/Intermedin Exerts Cardioprotective Effects by Regulating Cardiomyocyte Mitochondrial Function

BACKGROUND: Adrenomedullin 2 (AM2) plays critical roles in regulating blood pressure and fluid balance. However, the specific involvement of AM2 in cardiac hypertrophy has not been comprehensively elucidated, warranting further investigation into its molecular mechanisms and therapeutic implications. METHODS: Cardiac hypertrophy was induced in adult mice lacking AM2 (AM2−/−) using transverse aortic constriction surgery. Comprehensive cardiac morphology, function, histology, and transcriptome/metabolome analyses were conducted. Signal transduction underlying AM2 stimulation in the cardiomyocytes was explored. RESULTS: The absence of endogenous AM2 led to the development of severe heart failure after transverse aortic constriction surgery, which was characterized by alterations in the mitochondrial morphology and function associated with glycolysis and the tricarboxylic acid cycle in the heart and cardiomyocytes of transverse aortic constriction–operated AM2−/− mice. AM2 stimulation was associated with the receptor-modifying factor RAMP2 (receptor activity-modifying protein 2), which primarily transduces signals through the MAPK pathway and affects the expression of genes involved in glycolysis, β-oxidation, and oxidative phosphorylation. The administration of exogenous AM2 alleviated heart failure following transverse aortic constriction. CONCLUSIONS: AM2 crucially regulates mitochondrial functions associated with the glycolysis and tricarboxylic acid cycles in the cardiomyocytes, thereby exerting a protective effect on the heart under pressure overload conditions.