Abstract 13847: PTRF/Cavin-1 Knock-out Mice Develop a Progressive Cardiomyopathy with ERK1/2 Hyperactivation and Caveolin-3 Reduction
Background: Mutations in the PTRF gene, coding for Cavin-1, cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Symptoms of patients with CGL4 are more widespread comprising myopathy, smooth and skeletal muscle hypertrophy and osteopenia. In particular, patients with CGL4 due to PTRF/Cavin-1 mutations have fetal cardiac arrhythmia and long-QT syndrome. Patients with PTRF/Cavin-1 deficiency show reduction of Caveolin-3 (Cav3) whose deficiency leads to cardiac hypertrophy with loss of caveolae. However, it remains unknown whether loss of PTRF/Cavin-1 affects the phenotypic behavior cardiac myocytes in vitro. Here, we present a detailed characterization of the hearts of PTRF/Cavin-1 knock-out (KO) mice.
Methods and Results: PTRF/Cavin-1 KO mice developed a progressive cardiomyopathic phenotype. At four months of age, PTRF/Cavin-1 KO heats displayed significant wall thickness of left ventricles and reduced fractional shortening as revealed by echocardiography. Histological analysis revealed marked cardiomyocyte hypertrophy with progressive interstitial/peri-vascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF/Cavin-1 KO mice. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was significantly suppressed in PTRF/Cavin-1 KO hearts compared with wild-type hearts. Because Cav3 deletion-induced cardiac hypertrophy shows hyperactivation of p42/44 MAPK (ERK1/2) and loss of caveolae in cardiomyocytes, we assessed the ERK1/2 activity and caveolar morphology in the heart of PTRF/Cavin-1 KO mice. ERK1/2 was hyperactivated in PTRF/Cavin-1 KO hearts. Furthermore, electron microscopy displayed the absence of caveolae in cardiomyocytes of PTRF/Cavin-1 KO mice. However, small vesicles were retained in PTRF/Cavin-1 KO cardiomyocytes.
Conclusion: PTRF/Cavin-1 KO mice develop a progressive cardiomyopathy with ERK1/2 hyperactivation. Our results suggest that this process is attributable to Cav3 reduction. Our data argue that loss of PTRF/Cavin-1 expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy.
Author Disclosures: T. Kasahara: None. T. Ogata: None. N. Maruyama: None. T. Taniguchi: None. T. Hamaoka: None. K. Miyagawa: None. N. Nakanishi: None. T. Ueyama: None.
- © 2014 by American Heart Association, Inc.