TY - JOUR
T1 - Renalase is a novel target gene of hypoxia-inducible factor-1 in protection against cardiac ischaemia-reperfusion injury
AU - Du, Meng
AU - Huang, Kun
AU - Huang, Dan
AU - Yang, Liu
AU - Gao, Lu
AU - Wang, Xiaojing
AU - Huang, Dandan
AU - Li, Xiangrao
AU - Wang, Cheng
AU - Zhang, Fengxiao
AU - Wang, Yan
AU - Cheng, Min
AU - Tong, Qiangsong
AU - Qin, Gangjian
AU - Huang, Kai
AU - Wang, Lin
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (30971245 to K.H., 81000112 to D.H. and 81272559 to L.W.).
Publisher Copyright:
© 2014 The Author.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Aims Renalase, an enzyme that can metabolize catecholamine, was recently reported to attenuate the ischaemia/reperfusion (I/R)-induced cardiac injury. This work was undertaken to investigate the functions and regulation mechanisms of renalase in protection against cardiac I/R injury. Methods and results An elevated level of renalase was found in C57BL/6 mice challenged with I/R injury. Then, we generated a mouse model with cardiac administration of cholesterol-conjugated renalase siRNA followed by I/R operation. The mice treated with renalase siRNA exhibited increased infarction size and decreased cardiac function compared with the scramble siRNA group. Subsequently, we identified four potential hypoxia-inducible factor-1 alpha (HIF-1α)-binding motifs in the promoter of renalase through bioinformatics approaches. Dual-luciferase reporter assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and western blot were conducted and demonstrated that renalase was a novel target gene of HIF-1α. Furthermore, administration of renalase reduced the infarct area and rescued the deterioration of cardiac function in myocardial HIF-1α knockdown mice subjected to I/R injury. In addition, the levels of norepinephrine in serum as well as nicotinamide adenine dinucleotide (NAD+) and ATP in myocardium were determined, which implied that cardiac protection of renalase against I/R may be related, at least in part, to its metabolism of catecholamine and regulation of energy. Conclusion These findings have revealed renalase as a novel target gene of HIF-1α in protection against myocardial I/R injury, which provided a basis for therapeutic strategies for enhancing cardiomyocyte survival in patients associated with ischaemic heart diseases.
AB - Aims Renalase, an enzyme that can metabolize catecholamine, was recently reported to attenuate the ischaemia/reperfusion (I/R)-induced cardiac injury. This work was undertaken to investigate the functions and regulation mechanisms of renalase in protection against cardiac I/R injury. Methods and results An elevated level of renalase was found in C57BL/6 mice challenged with I/R injury. Then, we generated a mouse model with cardiac administration of cholesterol-conjugated renalase siRNA followed by I/R operation. The mice treated with renalase siRNA exhibited increased infarction size and decreased cardiac function compared with the scramble siRNA group. Subsequently, we identified four potential hypoxia-inducible factor-1 alpha (HIF-1α)-binding motifs in the promoter of renalase through bioinformatics approaches. Dual-luciferase reporter assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and western blot were conducted and demonstrated that renalase was a novel target gene of HIF-1α. Furthermore, administration of renalase reduced the infarct area and rescued the deterioration of cardiac function in myocardial HIF-1α knockdown mice subjected to I/R injury. In addition, the levels of norepinephrine in serum as well as nicotinamide adenine dinucleotide (NAD+) and ATP in myocardium were determined, which implied that cardiac protection of renalase against I/R may be related, at least in part, to its metabolism of catecholamine and regulation of energy. Conclusion These findings have revealed renalase as a novel target gene of HIF-1α in protection against myocardial I/R injury, which provided a basis for therapeutic strategies for enhancing cardiomyocyte survival in patients associated with ischaemic heart diseases.
KW - Hypoxia-inducible factor-1 alpha
KW - Ischaemia/reperfusion injury
KW - Renalase
KW - Transcriptional regulation
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U2 - 10.1093/cvr/cvu255
DO - 10.1093/cvr/cvu255
M3 - Article
C2 - 25497549
AN - SCOPUS:84922454014
VL - 105
SP - 182
EP - 191
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 2
ER -