title: A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain.
abstract: Familial hypertrophic cardiomyopathy (HCM) is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2) strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6) reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including β-myosin heavy chain (MHC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and skeletal muscle alpha actin (α1-actin). Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and α-smooth muscle actin (SMA)-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee HealthScience Center, Memphis, Tennessee, United States of America.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee HealthScience Center, Memphis, Tennessee, United States of America.
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee HealthScience Center, Memphis, Tennessee, United States of America.
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee HealthScience Center, Memphis, Tennessee, United States of America.
authors.forename: Fengbo
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee HealthScience Center, Memphis, Tennessee, United States of America.
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Jiangsu Key Laboratory of Neuroregenertion, Nantong University, Nantong, Jiangsu, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee HealthScience Center, Memphis, Tennessee, United States of America.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000199:Actins / Q000097:blood; D000818:Animals; D015415:Biomarkers; D001794:Blood Pressure; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D058628:Myofibroblasts / Q000473:pathology; D018995:Myosin Heavy Chains / Q000097:blood / Q000235:genetics*; D045265:Natriuretic Peptides / Q000097:blood; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D015415:Biomarkers; D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D045265:Natriuretic Peptides; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C; C551613:Myh7 protein, mouse