Novel Regulation of Cardiac Metabolism and Homeostasis by the Adrenomedullin-Receptor Activity-Modifying Protein 2 System
Novel Regulation of Cardiac Metabolism and Homeostasis by the Adrenomedullin-Receptor Activity-Modifying Protein 2 System
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DOI：
10.1161/hypertensionaha.111.00647
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发表时间：
2013-02-01
期刊：
影响因子：
8.3
通讯作者：
Shindo, Takayuki
中科院分区：
文献类型：
--
作者：
Yoshizawa, Takahiro;Sakurai, Takayuki;Shindo, Takayuki
肾上腺髓质素（Adrenomedullin，AM）是一种主要由心血管系统产生的血管舒张和扩张肽。AM受体降钙素受体样受体与受体活性修饰蛋白（RAMP）相关，RAMP是调节蛋白的亚型之一。在RAMP基因敲除小鼠（（-/-））中，只有RAMP 2（-/-）具有胚胎致死性，其心血管异常与AM（-/-）相同。这表明AM-RAMP 2系统对心血管系统特别重要。尽管AM和RAMP 2在胚胎至成年期的心脏中高度表达，但它们的分析受到AM（-/-）和RAMP 2（-/-）的胚胎致死性的限制。对于这项研究，我们产生了诱导型心肌细胞特异性RAMP 2（-/-）（C-RAMP 2（-/-））。C-RAMP 2-/-表现为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-RAMP 2（-/-）心脏还显示线粒体结构的变化和参与氧化磷酸化、β-氧化和活性氧调节的DAPRA相关基因的下调。此外，心力衰竭之前是过氧化物酶体增殖物激活受体-γ共激活因子1 α（PGC-1 α）的变化，PGC-1 α是线粒体生物发生的主要调节因子。代谢组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，心磷脂，线粒体膜特异性脂质的早期下调。此外，来自C-RAMP 2（-/-）的原代培养心肌细胞显示线粒体膜电位降低，并以RAMP 2缺失依赖性方式增加活性氧簇的产生。C-RAMP 2（-/-）显示下调cAMP反应元件结合蛋白（CREB）的活化，CREB是线粒体相关基因的主要调节物之一。这些数据表明，AM-RAMP 2系统是心脏代谢和稳态所必需的。AM-RAMP 2系统是心力衰竭的有前途的治疗靶点。（高血压。2013;61：341-351）。circle在线数据补充
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, beta-oxidation, and reactive oxygen species regulation. Furthermore, the heart failure was preceded by changes in peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha), 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. (Hypertension. 2013;61:341-351.) circle Online Data Supplement