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Circ Cardiovasc Genet. 2014 Apr;7(2):132-143. doi: 10.1161/CIRCGENETICS.113.000324. Epub 2014 Feb 28.

Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins.

Author information

1
Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
2
Department of Physiology and Department of Cell Biology, Federal University of Parana, Curitiba, Brazil.
3
Department of Physiology and Cell Biology, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH.
4
Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati.
5
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine.
6
Department of Medicine, Section of Cardiology, University of Illinois, Chicago, IL.
#
Contributed equally

Abstract

BACKGROUND:

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca(2+) sensitivity, and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype.

METHODS AND RESULTS:

We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca(2+) sensitivity, severe hypertrophy, and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca(2+) sensitivity in Tm180 mice by generating a double transgenic mouse line. We crossed Tm180 mice with mice expressing a pseudophosphorylated cardiac troponin I (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca(2+) sensitivity compared with wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in double transgenic compared with their Tm180 littermates, which express wild-type cardiac troponin I. Hearts of double transgenic mice demonstrated no changes in expression of phospholamban and sarcoplasmic reticulum Ca(2+) ATPase, increased levels of phospholamban and troponin T phosphorylation, and reduced phosphorylation of TnI compared with Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of extracellular signal-regulated kinase and zinc finger-containing transcription factor GATA in Tm180 hearts.

CONCLUSIONS:

Our data strongly indicate that reduction of myofilament sensitivity to Ca(2+) and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.

KEYWORDS:

cardiac remodeling; cardiomyopathies; cardiomyopathy, hypertrophic; therapeutics

PMID:
24585742
PMCID:
PMC4061696
DOI:
10.1161/CIRCGENETICS.113.000324
[Indexed for MEDLINE]
Free PMC Article

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