title: Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein.
abstract: We have recently shown that a temporary increase in sarcoplasmic reticulum (SR) cycling via adenovirus-mediated overexpression of sarcoplasmic reticulum ATPase (SERCA2) transiently improves relaxation and delays hypertrophic remodeling in a familial hypertrophic cardiomyopathy (FHC) caused by a mutation in the thin filament protein, tropomyosin (i.e., α-TmE180G or Tm180). In this study, we sought to permanently alter calcium fluxes via phospholamban (PLN) gene deletion in Tm180 mice in order to sustain long-term improvements in cardiac function and adverse cardiac remodeling/hypertrophy. While similar work has been done in FHCs resulting from mutations in thick myofilament proteins, no one has studied these effects in an FHC resulting from a thin filament protein mutation. Tm180 transgenic (TG) mice were crossbred with PLN knockout (KO) mice and four groups were studied in parallel: 1) non-TG (NTG), 2) Tm180, 3) PLNKO/NTG and 4) PLNKO/Tm180. Tm180 mice exhibit increased heart weight/body weight and hypertrophic gene markers compared to NTG mice, but levels in PLNKO/Tm180 mice were similar to NTG. Tm180 mice also displayed altered function as assessed via in situ pressure-volume analysis and echocardiography at 3-6 months and one year; however, altered function in Tm180 mice was rescued back to NTG levels in PLNKO/Tm180 mice. Collagen deposition, as assessed by Picrosirius Red staining, was increased in Tm180 mice but was similar in NTG and in PLNKO/Tm180 mice. Extracellular signal-regulated kinase (ERK1/2) phosphorylation increased in Tm180 mice while levels in PLNKO/Tm180 mice were similar to NTGs. The present study shows that by modulating SR calcium cycling, we were able to rescue many of the deleterious aspects of FHC caused by a mutation in the thin filament protein, Tm.
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, IL 60612, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gaffin
authors.forename: James R
authors.initials: JR
authors.lastname: Peña
authors.forename: Marco S L
authors.initials: MS
authors.lastname: Alves
authors.forename: Fernando A L
authors.initials: FA
authors.lastname: Dias
authors.forename: Shamim A K
authors.initials: SA
authors.lastname: Chowdhury
authors.forename: Lynley S
authors.initials: LS
authors.lastname: Heinrich
authors.forename: Paul H
authors.initials: PH
authors.lastname: Goldspink
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001835:Body Weight; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D004452:Echocardiography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D015415:Biomarkers; D002118:Calcium; D002135:Calcium-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D014335:Tropomyosin; D000099211:Phospholamban