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

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.

• Authors: 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
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 105 Issue 2 Pg. 182-91 (Feb 01 2015) ISSN: 1755-3245 [Electronic] England
• PMID: 25497549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: [email protected].

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Small Interfering
• Monoamine Oxidase
• renalase

Topics

• Animals
• Disease Models, Animal
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice, Inbred C57BL
• Monoamine Oxidase (genetics, metabolism)
• Myocardial Ischemia (genetics, therapy)
• Myocardial Reperfusion Injury (genetics, metabolism, therapy)
• Myocardium (metabolism)
• RNA, Small Interfering (genetics)