title: CXCR4 attenuates cardiomyocytes mitochondrial dysfunction to resist ischaemia-reperfusion injury.
abstract: The chemokine (C-X-C motif) receptor 4 (CXCR4) is expressed on native cardiomyocytes and can modulate isolated cardiomyocyte contractility. This study examines the role of CXCR4 in cardiomyocyte response to ischaemia-reperfusion (I/R) injury. Isolated adult rat ventricular cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) to simulate I/R injury. In response to H/R injury, the decrease in CXCR4 expression was associated with dysfunctional energy metabolism indicated by an increased adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratio. CXCR4-overexpressing cardiomyocytes were used to determine whether such overexpression (OE) can prevent bio-energetic disruption-associated cell death. CXCR4 OE was performed with adenoviral infection with CXCR4 encoding-gene or non-translated nucleotide sequence (Control). The increased CXCR4 expression was observed in cardiomyocytes post CXCR4-adenovirus transduction and this OE significantly reduced the cardiomyocyte contractility under basal conditions. Although the same extent of H/R-provoked cytosolic calcium overload was measured, the hydrogen peroxide-induced decay of mitochondrial membrane potential was suppressed in CXCR4 OE group compared with control group, and the mitochondrial swelling was significantly attenuated in CXCR4 group, implicating that CXCR4 OE prevents permeability transition pore opening exposure to overload calcium. Interestingly, this CXCR4-induced mitochondrial protective effect is associated with the enhanced signal transducer and activator of transcription 3 (expression in mitochondria. Consequently, in the presence of H/R, mitochondrial dysfunction was mitigated and cardiomyocyte death was decreased to 65% in the CXCR4 OE group as compared with the control group. I/R injury leads to the reduction in CXCR4 in cardiomyocytes associated with the dysfunctional energy metabolism, and CXCR4 OE can alleviate mitochondrial dysfunction to improve cardiomyocyte survival.
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Cai
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Liang
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Feng
authors.affiliation: Department of Pharmacology & Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Guan-Sheng
authors.initials: GS
authors.lastname: Liu
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Chang
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Wen
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Paul
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Meifeng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology & Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Millard
authors.affiliation: Department of Pathology & Lab Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; D002118:Calcium
keywords: CXCR4 overexpression; STAT3; cardiomyocytes; ischaemia/reperfusion injury; mitochondria
references.citation: Circ Res. 2008 Jan 4;102(1):131-5
references.pmid: 17967780
references.citation: Eur J Immunol. 2007 Oct;37(10):2949-60
references.pmid: 17853408
references.citation: J Card Fail. 2008 Jun;14(5):355-67
references.pmid: 18514926
references.citation: Science. 2009 Feb 6;323(5915):793-7
references.pmid: 19131594
references.citation: Am J Pathol. 2010 Apr;176(4):1705-15
references.pmid: 20133817
references.citation: Cardiovasc Res. 2010 Aug 1;87(3):406-23
references.pmid: 20448097
references.citation: Basic Res Cardiol. 2010 Sep;105(5):573-81
references.pmid: 20512582
references.citation: Basic Res Cardiol. 2010 Nov;105(6):771-85
references.pmid: 20960209
references.citation: J Cardiovasc Pharmacol. 2010 Nov;56(5):548-59
references.pmid: 20729750
references.citation: Science. 2010 Nov 19;330(6007):1066-71
references.pmid: 20929726
references.citation: Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1496-505
references.pmid: 21821779
references.citation: Circ Res. 2011 Nov 11;109(11):1302-8
references.pmid: 21980124
references.citation: Cardiovasc Res. 2012 May 1;94(2):333-41
references.pmid: 22411973
references.citation: J Mol Cell Cardiol. 2012 Aug;53(2):223-32
references.pmid: 22668785
references.citation: PLoS One. 2012;7(9):e46158
references.pmid: 23029422
references.citation: Circ Res. 2012 Oct 12;111(9):1222-36
references.pmid: 23065345
references.citation: J Clin Invest. 2013 Jan;123(1):92-100
references.pmid: 23281415
references.citation: Circ Res. 2013 Jan 4;112(1):79-89
references.pmid: 22982986
references.citation: J Biol Chem. 2013 Feb 15;288(7):4723-32
references.pmid: 23271731
references.citation: Basic Res Cardiol. 2013 Sep;108(5):377
references.pmid: 23917520
references.citation: Circ Res. 2013 Aug 16;113(5):603-16
references.pmid: 23948585
references.citation: Basic Res Cardiol. 2013 Sep;108(5):382
references.pmid: 24002083
references.citation: Curr Pharm Des. 2013;19(39):6890-5
references.pmid: 23590160
references.citation: Kidney Int. 2004 Aug;66(2):514-7
references.pmid: 15253700
references.citation: Cardiovasc Res. 2000 Sep;47(4):778-87
references.pmid: 10974226
references.citation: Basic Res Cardiol. 2014;109(6):440
references.pmid: 25236954
references.citation: J Mol Cell Cardiol. 2006 Nov;41(5):834-44
references.pmid: 17010372
references.citation: Transplant Proc. 2007 Mar;39(2):481-4
references.pmid: 17362763
references.citation: N Engl J Med. 2007 Sep 13;357(11):1121-35
references.pmid: 17855673
references.citation: J Mol Cell Cardiol. 2008 Feb;44(2):281-92
references.pmid: 18201717