Journal
CARDIOVASCULAR RESEARCH
Volume 97, Issue 1, Pages 44-54Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs294
Keywords
Genetics; Myozenin 2; Calcineurin; Hypertrophy; Sarcomere
Categories
Funding
- National Heart, Lung, and Blood Institute [R01-088498]
- National Institute of Aging [R21 AG038597]
- Burroughs Wellcome Award In Translational Research [1005907]
- Greater Houston Community Foundation (TexGen)
- George and Mary Josephine Hamman Foundation
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The role of calcineurin protein phosphatase 2B (PP2B) in the pathogenesis of human hypertrophic cardiomyopathy (HCM) remains unsettled. We determined potential involvement of calcineurin in the pathogenesis of HCM caused by mutations in myozenin 2 (MYOZ2), an inhibitor of calcineurin. We generated multiple lines of transgenic mice expressing either Flag-tagged wild-type (WT) (MYOZ2(WT)) or mutant MYOZ2(S48P) and MYOZ2(I246M), identified in families with HCM, in the heart. To mimic the human genotype, we generated bigenic mice expressing WT and mutant MYOZ2 in the background of hemizygous endogenous MYOZ2 (Myoz2(/)). Transgene proteins constituted 1548 of the total MYOZ2 protein in the heart. Mutant MYOZ2 mice showed molecular, cellular, and gross cardiac hypertrophy, preserved systolic function, and interstitial fibrosis. Immunofluorescence staining showed co-localization of WT and mutant MYOZ2 proteins with -actinin at the Z disks. Electron microscopy showed disrupted and mal-aligned Z disks in the mutant mice. Cardiac calcineurin activity, determined by quantifying Rcan1.4 mRNA and protein levels, luciferase activity in triple transgenic Myoz2(/):NFATc-Luc:MYOZ2(I246M) and Myoz2(/):NFATc-Luc:MYOZ2(WT) mice, and NFATc transcriptional activity assay, was unchanged in the mutant transgenic mice. However, levels of phospho-ERK1/2 and JNK54/46 were altered in the transgenic mice. Likewise, lentiviral-mediated expression of the MYOZ2(I246M) did not affect RCAN1.4 and calcineurin (PPP3CB) protein levels. Thus, the cardiac phenotype in HCM caused by MYOZ2 mutations might be independent of calcineurin activity in the heart. Z disk abnormalities might provide the stimulus for the induction of cardiac hypertrophy caused by MYOZ2 mutations.
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