title: Renalase is a novel target gene of hypoxia-inducible factor-1 in protection against cardiac ischaemia-reperfusion injury.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Du
authors.affiliation: Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Xiangrao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Medicine-Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Tarry 14-721, Chicago, IL 60611, USA.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China unionhlw@gmail.com huangkai1@mail.hust.edu.cn.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Medical Research Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan 430022, China Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., 430022, Wuhan, China unionhlw@gmail.com huangkai1@mail.hust.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000235:genetics* / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D009206:Myocardium / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D008995:Monoamine Oxidase; C521557:renalase
keywords: Hypoxia-inducible factor-1 alpha; Ischaemia/reperfusion injury; Renalase; Transcriptional regulation