Protection of Cardiomyocytes from Ischemic/Hypoxic Cell Death via Drbp1 and pMe2GlyDH in Cardio-specific ARC Transgenic Mice

• Published in: The Journal of biological chemistry 2008-11, Vol.283 (45), p.30707-30714
• Main Authors: Pyo, Jong-Ok, Nah, Jihoon, Kim, Hyo-Jin, Chang, Jae-Woong, Song, Young-Wha, Yang, Dong-Kwon, Jo, Dong-Gyu, Kim, Hyung-Ryong, Chae, Han-Jung, Chae, Soo-Wan, Hwang, Seung-Yong, Kim, Seung-Jun, Kim, Hyo-Joon, Cho, Chunghee, Oh, Chang-Gyu, Park, Woo Jin, Jung, Yong-Keun
• Format: Article
• Language: English
• Subjects: Animals; Cell Death - genetics; Cell Hypoxia - genetics; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Dimethylglycine Dehydrogenase - biosynthesis; Dimethylglycine Dehydrogenase - genetics; Enzyme Precursors - biosynthesis; Enzyme Precursors - genetics; Gene Expression Profiling; Gene Expression Regulation - genetics; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - pathology; Mechanisms of Signal Transduction; Mice; Mice, Transgenic; Mitochondrial Proteins - biosynthesis; Mitochondrial Proteins - genetics; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Organ Specificity - genetics; Protein Structure, Tertiary - genetics; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804209200

The ischemic death of cardiomyocytes is associated in heart disease and heart failure. However, the molecular mechanism underlying ischemic cell death is not well defined. To examine the function of apoptosis repressor with a caspase recruitment domain (ARC) in the ischemic/hypoxic damage of cardiomyocytes, we generated cardio-specific ARC transgenic mice using a mouse α-myosin heavy chain promoter. Compared with the control, the hearts of ARC transgenic mice showed a 3-fold overexpression of ARC. Langendoff preparation showed that the hearts isolated from ARC transgenic mice exhibited improved recovery of contractile performance during reperfusion. The cardiomyocytes cultured from neonatal ARC transgenic mice were significantly resistant to hypoxic cell death. Furthermore, the ARC C-terminal calcium-binding domain was as potent to protect cardiomyocytes from hypoxic cell death as ARC. Genome-wide RNA expression profiling uncovered a list of genes whose expression was changed (>2-fold) in ARC transgenic mice. Among them, expressional regulation of developmentally regulated RNA-binding protein 1 (Drbp1) or the dimethylglycine dehydrogenase precursor (pMe2GlyDH) affected hypoxic death of cardiomyocytes. These results suggest that ARC may protect cardiomyocytes from hypoxic cell death by regulating its downstream, Drbp1 and pMe2GlyDH, shedding new insights into the protection of heart from hypoxic damages.