title: Cardiac-specific NRAP overexpression causes right ventricular dysfunction in mice.
abstract: The muscle-specific protein NRAP is concentrated at cardiac intercalated disks, plays a role in myofibril assembly, and is upregulated early in mouse models of dilated cardiomyopathy. Using a tet-off system, we developed novel transgenic lines exhibiting cardiac-specific NRAP overexpression ~2.5 times greater than normal. At 40-50 weeks, NRAP overexpression resulted in dilation and decreased ejection fraction in the right ventricle, with little effect on the left ventricle. Expression of transcripts encoding brain natriuretic peptide and skeletal α-actin was increased by cardiac-specific NRAP overexpression, indicative of a cardiomyopathic response. NRAP overexpression did not alter the levels or organization of N-cadherin and connexin-43. The results show that chronic NRAP overexpression in the mouse leads to right ventricular cardiomyopathy by 10 months, but that the early NRAP upregulation previously observed in some mouse models of dilated cardiomyopathy is unlikely to account for the remodeling of intercalated disks and left ventricular dysfunction observed in those cases.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Shajia
authors.initials: S
authors.lastname: Lu
authors.forename: Garland L
authors.initials: GL
authors.lastname: Crawford
authors.forename: Justin
authors.initials: J
authors.lastname: Dore
authors.forename: Stasia A
authors.initials: SA
authors.lastname: Anderson
authors.forename: Daryl
authors.initials: D
authors.lastname: Despres
authors.forename: Robert
authors.initials: R
authors.lastname: Horowits
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D004452:Echocardiography; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes; D018497:Ventricular Dysfunction, Right / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D009124:Muscle Proteins; C491567:Nrap protein, mouse