Renalase is a novel target gene of hypoxia-inducible factor-1 in protection against cardiac ischaemia-reperfusion injury

Meng Du, Kun Huang, Dan Huang, Liu Yang, Lu Gao, Xiaojing Wang, Dandan Huang, Xiangrao Li, Cheng Wang, Fengxiao Zhang, Yan Wang, Min Cheng, Qiangsong Tong, Gangjian Qin, Kai Huang, Lin Wang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)182-191
Number of pages10
JournalCardiovascular Research
Volume105
Issue number2
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Keywords

  • Hypoxia-inducible factor-1 alpha
  • Ischaemia/reperfusion injury
  • Renalase
  • Transcriptional regulation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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