Abstract 12559: Adrenomedullin-RAMP2 System is Essential For Cardiac Homeostasis
Adrenomedullin (AM) is a peptide, which is mainly produced in the cardiovascular system and involved in both the pathogenesis of cardiovascular diseases and homeostasis. AM knockout mice (AM-/-) are embryonic lethal at midgestation by abnormalities of cardiovascular development (Circulation. 2002). AM and its family peptides share the same receptor, named calcitonin receptor-like receptor (CLR). CLR associates with accessory proteins, named receptor activity-modifying protein (RAMP). So far, 3 RAMP subtypes are identified. Among knockout mice of RAMPs, only RAMP2-/- are embryonic lethal and reproduce the phenotype of AM-/- (J Clin Invest. 2008). AM and RAMP2 are also expressed in the heart, however their function is not clearly demonstrated because of the embryonic lethality of both AM-/- and RAMP2-/-. In this study, we generated cardiac myocyte-specific RAMP2 knockout mice (C-RAMP2-/-) using αMHC-MerCreMer mice. In this model, we can induce the gene deletion in adult stage. C-RAMP2-/- mice showed dilated cardiomyopathy-like heart failure with cardiac dilatation and disarray of myofibrils after induction of the gene-deletion. We found abnormality of mitochondrial structure in electron microscopic observation. In RT-realtime-PCR, we also found down-regulation of mitochondrial regulatory factor, PGC-1. Next, we performed MALDI-TOF-MS analysis and found that cardiolipin, mitochondrial inner membrane specific lipid, was decreased in C-RAMP2-/-. Primary-cultured cardiac myocytes showed reduced mitochondrial-membrane potential and increased mitochondrial ROS production in RAMP2-deletion dependent manner. C-RAMP2-/- showed the down-regulated activation of CREB, one of the main regulator of mitochondria-related genes. In C-RAMP2-/-, many CREB related signaling pathway was down-regulated. Finally, we tried recovery of CREB activation. Forskolin-treatment recovered the cardiac remodeling, CREB activity, and the expression of mitochondria-related genes. In conclusion, we found AM-RAMP2 system is essential for cardiac homeostasis through the regulation of mitochondrial function. AM-RAMP2 system could be a novel therapeutic target of heart failure in future.
- © 2011 by American Heart Association, Inc.