title: Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins.
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.
  
  
  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.
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.|Department of Physiology and Department of Cell Biology, Federal University of Parana, Curitiba, Brazil.
authors.forename: Marco L
authors.initials: ML
authors.lastname: Alves
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.|Department of Physiology and Department of Cell Biology, Federal University of Parana, Curitiba, Brazil.
authors.forename: Fernando A L
authors.initials: FAL
authors.lastname: Dias
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gaffin
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Jillian N
authors.initials: JN
authors.lastname: Simon
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Montminy
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.|Department of Physiology and Cell Biology, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Biesiadecki
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Hinken
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Utter
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Davis
authors.affiliation: Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati.
authors.forename: Sadayappan
authors.initials: S
authors.lastname: Sakthivel
authors.affiliation: Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine.
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.affiliation: Department of Medicine, Section of Cardiology, University of Illinois, Chicago, IL.|Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009210:Myofibrils / Q000378:metabolism*; D010766:Phosphorylation; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism; D019210:Troponin I / Q000235:genetics* / Q000378:metabolism; D020107:Troponin T / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D014335:Tropomyosin; D019210:Troponin I; D020107:Troponin T; D000099211:Phospholamban
keywords: cardiac remodeling; cardiomyopathies; cardiomyopathy, hypertrophic; therapeutics