Abstract 16817: Overexpression of CARP Exaggerates Cardiac Hypertrophy and Heart Failure by Accumulation of Calcineurin and p53 in Pressure-Overloaded Mice
Background:It is known that the muscle ankyrin repeat protein family member Ankrd1/CARP is markedly augmented in cardiac hypertrophy and heart failure (HF). But, its role and the underlying mechanisms the pathogenesis of cardiac hypertrophy and HF remain unclear. Recently CARP was identified as a co-activator of p53, while p53 was demonstrated to play an important role in the progression of HF. We therefore hypothesized that CARP would accelerate HF by activation of p53.
Methods and Results: In transverse aortic constriction (TAC) mouse models, cardiac-restricted overexpression of adenoviral CARP (Ad-CARP, myocardial injection) markedly increased heart to body weight ratio (5.81±0.20 mg/g in TAC-Ad-EGFP group, 8.88±1.54 mg/g in Ad-CARP group, P<0.01) and accelerated cardiac dysfunction (left ventricular fractional shortening:35.69%±4.33% in Ad-EGFP group,26.21%±4.16% in Ad-CARP group, P<0.01; lung to body weight ratio: 6.69±1.10mg/g in TAC-Ad-EGFP group, 12.17±3.21 mg/g in Ad-CARP group, P<0.05). In Ad-CARP treated mice, myocardial protein expression of p53, phosphorylated p53, Bax and calcineurin was significantly increased. In Ad-CARP transfected cultured neonatal rat cardiomyocytes, angiotensin II (Ang-II)- induced myocyte hypertrophy was enhanced (the cardiomyocytes area: 63.38±16.45 um2 verse 47.06±13.10 um2, P<0.01) and the upregulation of atrial natriuretic peptide and β-myosin heavy chain gene expression was strengthened. Moreover, we noted that overexpression of CARP in cultured cardiomyocytes increased mitochondrial permeability determined by fluorescence intensity of tetramethylrhodamine ethyl ester, upregulated protein level of p-p53, Bax and calcineurin, reduced cell viability measured by MTT assay and increased cell apoptosis detected by Hoechst stain. CARP upregulation in both Ang-II-stimulated cultured cardiomyocytes and heart of TAC mice was obviously abrogated by pretreatment with Ang-II receptor I blocker olmersartan.
Conclusion: These findings indicate that CARP worsens cardiac hypertrophy and heart failure by upregulation of calcineurin and p53 and induction of cardiomyocyte apoptosis, implicating that CARP is a potential therapeutic target of cardiac hypertrophy and failure.
- © 2012 by American Heart Association, Inc.