A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain.

Wenyuan Zhao,Robert W Williams,Yuanjian Chen,Syamal K Bhattacharya,Qingqing Gu,Lu Lu,Tieqiang Zhao,Yao Sun,Fengbo Zhao,Nikolaos Frangogiannis

doi:10.1371/journal.pone.0133132

Wenyuan Zhao, Robert W Williams + Show 8 more

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https://doi.org/10.1371/journal.pone.0133132

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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.

Highlights

Hypertrophic cardiomyopathy is a common heart disease that affects about one out of 500 humans
40% of these mutations occur in the the cardiac myosin binding protein C gene (Mybpc3), while about 40% involve β-myosin heavy chain (MHC) (Myh7)
Based on the sequence of B6 and D2 strains, we found that D2 mice had sequence variants in Mybpc3 and Myh7, compared to B6 mice

Summary

Introduction

Hypertrophic cardiomyopathy is a common heart disease that affects about one out of 500 humans It occurs in a non-dilated ventricle in the absence of other cardiac pathologies capable of producing the observed magnitude of increased left ventricular wall thickness, such as PLOS ONE | DOI:10.1371/journal.pone.0133132. HCM is most commonly associated with a mutation of sarcomeric genes that results in a mutated protein in the sarcomere, the primary component of cardiomyocytes [4]. These are predominantly single-point missense mutations in the genes for myosin-binding protein C (Mybpc3), β-MHC (myh7), cardiac troponin T (Tnnt2), etc. In individuals without a family history of HCM, the most common cause of the disease is a de novo mutation of the gene that produces β-MHC

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