Adrenomedullin-RAMP2 and-RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress
Adrenomedullin-RAMP2 and-RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress
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DOI：
10.1210/endocr/bqab001
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发表时间：
2021-01-06
期刊：
影响因子：
4.8
通讯作者：
Shindo, Takayuki
中科院分区：
文献类型：
--
作者：
Cui, Nanqi;Sakurai, Takayuki;Shindo, Takayuki
肾上腺髓质素（AM）是一种具有多种生理功能的肽激素，受其受体活性修饰蛋白RAMP2和RAMP3调控。我们之前报道过AM或RAMP2敲除（KO） （AM-/-, RAMP2-/-）在小鼠胚胎中是致命的，而RAMP3-/-小鼠显然是正常的。AM、RAMP2、RAMP3均在心脏高表达；然而，它们在那里的功能还没有被完全理解。在此，我们分析了AM-RAMP2和AM-RAMP3系统在心血管应激心脏中的病理生理功能。心肌细胞特异性RAMP2-/- (C-RAMP2-/-)和RAMP3-/-在基线时未出现明显的心力衰竭。然而，在横断主动脉收缩（TAC） 1周后，与野生型小鼠相比，C-RAMP2-/-表现出明显的心脏肥厚、射血分数降低和纤维化增加。C-RAMP2-/-的dP/dtmax和dP/dtmin均显著降低，表明心室收缩性和舒张性降低。与野生型细胞相比，将C-RAMP2-/-心肌细胞暴露于异丙肾上腺素中可增强其肥大和氧化应激。C-RAMP2-/-心肌细胞也含有更少的活线粒体，并显示线粒体减少！膜电位和呼吸能力。RAMP3-/-在TAC后也表现出收缩功能降低和纤维化增强，但这些仅在4周后才变得明显。心脏淋巴管减少是RAMP3-/-的特征性特征。这些观察结果表明，AM-RAMP2系统通过调节心脏线粒体对心血管应激的早期适应是必要的。AM-RAMP3是通过调节淋巴管进行后期适应所必需的。因此，AM-RAMP2和AM-RAMP3系统在维持心血管稳态对抗心血管应激方面发挥着各自的关键作用。
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 mitochondria! 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.