PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis

Abstract

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.

Muscular dystrophy in PTFR/cavin-1 null mice

“…Muscle hypertrophy is also characteristic of human PTRF/cavin-1 deficiency (5, 8). In addition, hypertrophic cardiomyopathy has been reported in human CAV3 mutations (57) and in Cav3 null mice (58), as well as in cavin-1 null mice (59). It should be noted, however, that while PTRF mutations in mice and humans result in total loss of protein, most (or all) human CAV3 mutations encode altered proteins that are expressed and can act in a dominant-negative fashion, causing alterations/loss of caveolar structures.…”

Caveolin as a Novel Potential Therapeutic Target in Cardiac and Vascular Diseases: A Mini Review

“…In addition, incubation with caveolin-3 adenovirus promotes the expression of caveolin-3 and ANP and the phosphorylation of Akt in cardiac myocytes [51]. According to Taniguchi T et al, [52] the loss of PTRF/cavin-1 protein expression is sufficient to induce a molecular program that leads to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to caveolin-3 reduction in the heart. Moreover, according to Lei et al [53], caveolin-3 has been shown to exert a cardio-protective function against hyperglycemia-induced cardiac function; furthermore, hyperglycemia-induced excessive PKCβ2 activation reduces caveolin-3 expression and subsequently reduces Akt signaling, detrimentally affecting cardiac remodeling and function.…”

Cardiac-Specific Expression of ΔH2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy

“…66 Cavin-1 is particularly interesting because several recent studies suggest that cavin-1 deficiency contributes to the pathogenesis of cardiomyopathy and muscular dystrophy. [72][73][74] An intriguing finding of this study is the presence of myocardial hypertrophy in aMHC.DH2-R15 mice ( Table 1). While the molecular trigger for cardiac hypertrophy in aMHC.DH2-R15 mice remains elusive ( Fig.…”