Faculty Collaboration Database

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. J Mol Cell Cardiol 2011 Nov;51(5):812-20

Date

08/16/2011

Pubmed ID

21840315

Pubmed Central ID

PMC3221410

DOI

10.1016/j.yjmcc.2011.07.026

Scopus ID

2-s2.0-80053236880 (requires institutional sign-in at Scopus site)   34 Citations

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.

Author List

Gaffin RD, Peña JR, Alves MS, Dias FA, Chowdhury SA, Heinrich LS, Goldspink PH, Kranias EG, Wieczorek DF, Wolska BM

MESH terms used to index this publication - Major topics in bold

Animals
Biomarkers
Body Weight
Calcium
Calcium-Binding Proteins
Cardiomyopathy, Hypertrophic, Familial
Disease Models, Animal
Echocardiography
Extracellular Signal-Regulated MAP Kinases
Gene Expression
Humans
Mice
Mice, Transgenic
Mutation
Myocardial Contraction
Myocardium
Organ Size
Phosphorylation
Real-Time Polymerase Chain Reaction
Sarcoplasmic Reticulum
Tropomyosin