Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano, 390-8621, Japan.
Hypertension. 2013 Feb;61(2):341-51. doi: 10.1161/HYPERTENSIONAHA.111.00647. Epub 2013 Jan 7.
Adrenomedullin (AM) was identified as a vasodilating and hypotensive peptide mainly produced by the cardiovascular system. The AM receptor calcitonin receptor-like receptor associates with receptor activity-modifying protein (RAMP), one of the subtypes of regulatory proteins. Among knockout mice ((-/-)) of RAMPs, only RAMP2(-/-) is embryonically lethal with cardiovascular abnormalities that are the same as AM(-/-). This suggests that the AM-RAMP2 system is particularly important for the cardiovascular system. Although AM and RAMP2 are highly expressed in the heart from embryo to adulthood, their analysis has been limited by the embryonic lethality of AM(-/-) and RAMP2(-/-). For this study, we generated inducible cardiac myocyte-specific RAMP2(-/-) (C-RAMP2(-/-)). C-RAMP2(-/-) exhibited dilated cardiomyopathy-like heart failure with cardiac dilatation and myofibril disruption. C-RAMP2(-/-) hearts also showed changes in mitochondrial structure and downregulation of mitochondria-related genes involved in oxidative phosphorylation, β-oxidation, and reactive oxygen species regulation. Furthermore, the heart failure was preceded by changes in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. Metabolome and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) imaging analyses revealed early downregulation of cardiolipin, a mitochondrial membrane-specific lipid. Furthermore, primary-cultured cardiac myocytes from C-RAMP2(-/-) showed reduced mitochondrial membrane potential and enhanced reactive oxygen species production in a RAMP2 deletion-dependent manner. C-RAMP2(-/-) showed downregulated activation of cAMP response element binding protein (CREB), one of the main regulators of mitochondria-related genes. These data demonstrate that the AM-RAMP2 system is essential for cardiac metabolism and homeostasis. The AM-RAMP2 system is a promising therapeutic target of heart failure.
肾上腺髓质素（AM）被鉴定为一种主要由心血管系统产生的血管扩张和降压肽。AM 受体降钙素受体样受体与受体活性修饰蛋白（RAMP）相关联，RAMP 是调节蛋白的亚型之一。在 RAMP 敲除小鼠（（-/-））中，只有 RAMP2（-/-）具有胚胎致死性，并伴有与 AM（-/-）相同的心血管异常。这表明 AM-RAMP2 系统对心血管系统尤为重要。尽管 AM 和 RAMP2 在胚胎到成年期的心脏中高度表达，但由于 AM（-/-）和 RAMP2（-/-）的胚胎致死性，对它们的分析受到限制。在这项研究中，我们产生了诱导型心肌细胞特异性 RAMP2（-/-）（C-RAMP2（-/-））。C-RAMP2（-/-）表现出扩张型心肌病样心力衰竭，伴有心脏扩张和肌原纤维破坏。C-RAMP2（-/-）心脏还表现出线粒体结构的变化，以及涉及氧化磷酸化、β-氧化和活性氧调节的线粒体相关基因的下调。此外，心力衰竭之前发生过过氧化物酶体增殖物激活受体-γ共激活因子 1α（PGC-1α）的变化，PGC-1α 是线粒体生物发生的主要调节因子。代谢组学和基质辅助激光解吸/电离飞行时间质谱（MALDI-TOF-MS）成像分析显示，早期下调了一种线粒体膜特异性脂质心磷脂。此外，C-RAMP2（-/-）的原代心肌细胞表现出依赖于 RAMP2 缺失的线粒体膜电位降低和活性氧产生增强。C-RAMP2（-/-）显示 cAMP 反应元件结合蛋白（CREB）的激活下调，CREB 是线粒体相关基因的主要调节因子之一。这些数据表明，AM-RAMP2 系统对心脏代谢和稳态至关重要。AM-RAMP2 系统是心力衰竭的一个有前途的治疗靶点。
