Qing He1, Jun Pu2, Ancai Yuan1, Wayne Bond Lau1, Erhe Gao1, Walter J Koch1, Xin-Liang Ma2, Ben He2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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: Eric D Bischoff; Chris L Daige; Mary Petrowski; Harry Dedman; Jennifer Pattison; Joseph Juliano; Andrew C Li; Ira G Schulman Journal: J Lipid Res Date: 2010-05 Impact factor: 5.922
Authors: N P Hessvik; M V Boekschoten; M A Baltzersen; S Kersten; X Xu; H Andersén; A C Rustan; G H Thoresen Journal: Am J Physiol Endocrinol Metab Date: 2009-12-08 Impact factor: 4.310
Authors: Christopher Lotz; Maria Lazariotto; Andreas Redel; Thorsten M Smul; Jan Stumpner; Christoph Blomeyer; Tobias Tischer-Zeitz; Johannes Schmidt; Joanna Pociej; Norbert Roewer; Franz Kehl; Markus Lange Journal: Exp Biol Med (Maywood) Date: 2010-12-16
Authors: A J C Pommier; G Alves; E Viennois; S Bernard; Y Communal; B Sion; G Marceau; C Damon; K Mouzat; F Caira; S Baron; J M A Lobaccaro Journal: Oncogene Date: 2010-03-01 Impact factor: 9.867
Authors: Michael Spyridon; Leonardo A Moraes; Chris I Jones; Tanya Sage; Parvathy Sasikumar; Giovanna Bucci; Jonathan M Gibbins Journal: Blood Date: 2011-03-16 Impact factor: 22.113
Authors: Irma Kuipers; Jiang Li; Inge Vreeswijk-Baudoin; Johan Koster; Pim van der Harst; Herman H W Silljé; Folkert Kuipers; Dirk J van Veldhuisen; Wiek H van Gilst; Rudolf A de Boer Journal: Eur J Heart Fail Date: 2010-06-29 Impact factor: 15.534
Authors: Ali Javaheri; Ahmed Diab; Lei Zhao; Chenao Qian; Jordana B Cohen; Payman Zamani; Anupam Kumar; Zhaoqing Wang; Christina Ebert; Joseph Maranville; Erika Kvikstad; Michael Basso; Vanessa van Empel; A Mark Richards; Robert N Doughty; Ernst Rietzschel; Karl Kammerhoff; Joseph Gogain; Peter Schafer; Dietmar A Seiffert; David A Gordon; Francisco Ramirez-Valle; Douglas L Mann; Thomas P Cappola; Julio A Chirinos Journal: Circ Heart Fail Date: 2022-08-09 Impact factor: 10.447