Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress

Abstract Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity–modifying proteins, RAMP2 and RAMP3. We previously reported that AM or knockout (KO) (AM–/–, RAMP2–/–) embryonically lethal in mice, whereas RAMP3–/– mice apparently normal. AM, RAMP2, RAMP3 all highly expressed the heart; however, their functions there not fully understood. Here, we analyzed pathophysiological of AM-RAMP2 AM-RAMP3 systems hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2–/– (C-RAMP2–/–) showed no apparent heart failure at base line. After 1 week transverse aortic constriction (TAC), C-RAMP2–/– exhibited significant cardiac hypertrophy, decreased ejection fraction, increased fibrosis compared wild-type mice. Both dP/dtmax dP/dtmin were significantly reduced C-RAMP2–/–, indicating ventricular contractility relaxation. Exposing cardiomyocytes isoproterenol enhanced hypertrophy oxidative stress cells. also contained fewer viable mitochondria mitochondrial membrane potential respiratory capacity. systolic function after TAC, but those only became 4 weeks. A reduction lymphatic vessels was characteristic feature RAMP3–/–. These observations indicate system necessary for early adaptation through regulation mitochondria. later vessels. The thus play separate critical roles maintenance homeostasis against