title: Activation of liver-X-receptor α but not liver-X-receptor β protects against myocardial ischemia/reperfusion injury.
abstract: BACKGROUND
  Liver-X-receptors, LXRα (NR1H3) and LXRβ (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXRα and LXRβ subtypes have discrete roles in the regulation of cardiac physiology/pathology is unknown. We determine the role of each LXR subtype in myocardial ischemia/reperfusion (MI/R) injury.
  
  
  RESULTS
  Mice (wild type; those genetically depleted of LXRα, LXRβ, or both; and those overexpressing LXRα or LXRβ by in vivo intramyocardial adenoviral vector) were subjected to MI/R injury. Both LXRα and LXRβ were detected in wild-type mouse heart. LXRα, but not LXRβ, was significantly upregulated after MI/R. Dual activation of LXRα and LXRβ by natural and synthetic agonists reduced myocardial infarction and improved contractile function after MI/R. Mechanistically, LXR activation inhibited MI/R-induced oxidative stress and nitrative stress, attenuated endoplasmic reticulum stress and mitochondrial dysfunction, and reduced cardiomyocyte apoptosis in ischemic/reperfused myocardium. The aforementioned cardioprotective effects of LXR agonists were impaired in the setting of cardiac-specific gene silencing of LXRα, but not LXRβ subtype. Moreover, LXRα/β double-knockout and LXRα-knockout mice, but not LXRβ-knockout mice, increased MI/R injury, exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic reticulum stress and mitochondrial dysfunction. Furthermore, cardiac LXRα, not LXRβ, overexpression via adenoviral transfection suppressed MI/R injury.
  
  
  CONCLUSIONS
  Our study provides the first direct evidence that the LXRα, but not LXRβ, subtype is a novel endogenous cardiac protective receptor against MI/R injury. Drug development strategies specifically targeting LXRα may be beneficial in treating ischemic heart disease.
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.). pujun310@hotmail.com heben1026@hotmail.com xin.ma@Jefferson.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Ancai
authors.initials: A
authors.lastname: Yuan
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.). pujun310@hotmail.com heben1026@hotmail.com xin.ma@Jefferson.edu.
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
authors.affiliation: From the Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Q.H., J.P., A.Y., B.H.); Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.B.L., X.-L.M.); and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (E.G., W.J.K.). pujun310@hotmail.com heben1026@hotmail.com xin.ma@Jefferson.edu.
authors.forename: Ben
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000502:physiology; D020868:Gene Silencing; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D020033:Protein Isoforms; D015854:Up-Regulation
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; C000605211:Nr1h2 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms
keywords: apoptosis; myocardium; receptors, cytoplasmic and nuclear; reperfusion injury