1 Citation 170 Views 21 Downloads
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 (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 one week of transverse
aortic constriction (TAC), however, C-RAMP2-/- exhibited significant
cardiac hypertrophy, decreased ejection fraction and increased fibrosis as
compared to 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 as compared to 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.
170 views reported since publication in 2020.