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    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 RAMP2 knockout (KO) (AM-/-, RAMP2-/-) is embryonically lethal in mice, whereas RAMP3-/- mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2-/- (C-RAMP2-/-) and RAMP3-/- showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2-/- exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP/dtmax and dP/dtmin were significantly reduced in C-RAMP2-/-, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2-/- cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2-/- cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3-/- also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3-/-. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress. © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail:


    Nanqi Cui, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Megumu Tanaka, Masaaki Tanaka, Yangxuan Wei, Shinji Kakihara, Yunlu Zhao, Kohsuke Aruga, Hiroyuki Kawagishi, Tsutomu Nakada, Mitsuhiko Yamada, Takayuki Shindo. Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress. Endocrinology. 2021 Mar 01;162(3)

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    PMID: 33545715

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