title: Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.
abstract: We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jessica Jen-Chu
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rau
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Rozeta
authors.initials: R
authors.lastname: Avetisyan
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Milagros C
authors.initials: MC
authors.lastname: Romay
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Gabriel
authors.identifier: 0000-0002-8196-1561
authors.initials: G
authors.lastname: Stolin
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ke Wei
authors.initials: KW
authors.lastname: Gong
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D037502:Galectin 3 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D024462:Myosin Type II / Q000096:biosynthesis* / Q000235:genetics; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis* / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D037502:Galectin 3; C485095:Lgals3 protein, mouse; C483905:Myh14 protein, mouse; D020097:Natriuretic Peptide, Brain; D024462:Myosin Type II; D018995:Myosin Heavy Chains; D007545:Isoproterenol