title: A systems genetics approach identifiesTrp53inp2as a link between cardiomyocyte glucose utilization and hypertrophic response.
abstract: Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the geneTrp53inp2as a cardiomyocyte glucose utilization-specific factor.Trp53inp2gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude thatTrp53inp2serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHYHere, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identifyTrp53inp2as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Marcus M
authors.identifier: http://orcid.org/0000-0002-8785-0766
authors.initials: MM
authors.lastname: Seldin
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Kim
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Milagros C
authors.initials: MC
authors.lastname: Romay
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Shen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, University of California Los Angeles, Los Angeles, California.
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Rau
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Karthickeyan Chella
authors.initials: KC
authors.lastname: Krishnan
authors.affiliation: Department of Anesthesiology, University of California Los Angeles, Los Angeles, California.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and.
authors.forename: Arjun
authors.initials: A
authors.lastname: Deb
authors.affiliation: Department of Medicine, Cardiology Division at the University of California Los Angeles, Los Angeles, California; and jlusis@mednet.ucla.edu.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D002316:Cardiotonic Agents; D048429:Cell Size; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D066298:In Vitro Techniques; D007545:Isoproterenol; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002316:Cardiotonic Agents; D034741:RNA, Small Interfering; C000621549:Tp53inp2 protein, rat; D014157:Transcription Factors; D006003:Glycogen; D005947:Glucose; D007545:Isoproterenol
keywords: Trp53inp2; glucose; hypertrophy; metabolic shift