Open AccessPTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis
Author(s) -
Tetsuo Taniguchi,
Naoki Maruyama,
Toru Ogata,
Takeru Kasahara,
Naohiko Nakanishi,
Kotaro Miyagawa,
Daisuke Naito,
Toshiyuki Hamaoka,
Masahiro Nishi,
Satoaki Matoba,
Tomomi Ueyama
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0162513
Subject(s) - medicine , myocyte , intercalated disc , biology , cardiomyopathy , blot , heart failure , cardiology , gene , microbiology and biotechnology , genetics , intracellular , gap junction
Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF / Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF / Cavin-1 -null ( PTRF −/− ) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF −/− mice. PTRF −/− mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF −/− mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF −/− hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF −/− hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF −/− hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart.