title: Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice.
abstract: We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes. Adamts2 silencing regulated the expression of the genes residing within the module and impaired isoproterenol-induced cellular hypertrophy. Our results provide a view of higher order interactions in heart failure with potential for diagnostic and therapeutic insights.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Rau
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Milagros C
authors.initials: MC
authors.lastname: Romay
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Tuteryan
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jessica J-C
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Center for Interdisciplinary Research on Complex Systems, Department of Physics, Northeastern University, Boston, MA 02115, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Santolini
authors.affiliation: Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: Center for Interdisciplinary Research on Complex Systems, Department of Physics, Northeastern University, Boston, MA 02115, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Karma
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jlusis@mednet.ucla.edu.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics* / Q000502:physiology; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000009:adverse effects; D002395:Catecholamines / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D006333:Heart Failure / Q000235:genetics; D006352:Heart Ventricles / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology / Q000379:methods*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; D002395:Catecholamines; D000071096:ADAMTS Proteins; C000609308:Adamts2 protein, mouse; D007545:Isoproterenol
keywords: MICA; causal modeling; gene network; siRNA mediated knockdown; ventricular myocytes