Abstract
The gene ankyrin repeat domain 1 (Ankrd1) is an enigmatic gene and may exert pleiotropic function dependent on its expression level, subcellular localization and even types of pathological stress, but it remains unclear how these factors influence the fate of cardiomyocytes. Here we attempted to investigate the role of CARP on cardiomyocyte hypertrophy. In neonatal rat ventricular cardiomyocytes (NRVCs), angiotensin II (Ang II) increased the expression of both calpain 1 and CARP, and also induced cytosolic translocation of CARP, which was abrogated by a calpain inhibitor. In the presence of Ang-II in NRVCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced myocyte hypertrophy, the upregulation of atrial natriuretic peptide and β-myosin heavy chain genes and calcineurin proteins as well as nuclear translocation of nuclear factor of activated T cells. Cyclosporin A attenuated Ad-Ankrd1-enhanced cardiomyocyte hypertrophy. Intra-myocardial injection of Ad-Ankrd1 in mice with transverse aortic constriction (TAC) markedly increased the cytosolic CARP level, the heart weight/body weight ratio, while short hairpin RNA targeting Ankrd1 inhibited TAC-induced hypertrophy. The expression of calcineurin was also significantly increased in Ad-Ankrd1-infected TAC mice. Olmesartan (an Ang II receptor antagonist) prevented the upregulation of CARP in both Ang II-stimulated NRVCs and hearts with pressure overload. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac remodeling through the enhancement of cytosolic translocation of CARP and upregulation of calcineurin.
Highlights
Cardiac ankyrin repeat protein (CARP) binds to various proteins, such as titin/connectin, myopalladin [1], and calsequestrin [2], and it plays a critical role in the maintenance of sarcomere integrity, stretch sensing, and excitation-contraction coupling under physiological and pathological conditions
CARP was mainly localized to the nucleus under basal conditions, cytoplasmic translocation of CARP was noted when angiotensin II (Ang II) treatment for 24 h in neonatal rat ventricular cardiomyocytes (NRVCs), which was abolished by a calpain 1 inhibitor (Fig. 2B), suggesting that cytosolic retention of CARP contributes to Ang II-induced cardiomyocyte hypertrophy
It has been demonstrated that ankyrin repeat domain 1 (Ankrd1)/CARP expression is upregulated in response to myocardial damage and dysfunction regardless of the etiology [3,4,6], and elevation of Ankrd1/CARP expression is interpreted as an indicator of an unfavorable clinical outcome, it remains unclear whether myocardial overexpression of Ankrd1 in cardiac hypertrophy is causally related to the development of a malignant cardiac phenotype or whether it is merely an adaptive response that delays the progression of cardiac hypertrophy
Summary
Cardiac ankyrin repeat protein (CARP) binds to various proteins, such as titin/connectin, myopalladin [1], and calsequestrin [2], and it plays a critical role in the maintenance of sarcomere integrity, stretch sensing, and excitation-contraction coupling under physiological and pathological conditions. Subcellular distribution of CARP is thought to be associated with its different function [11], while the cytosolic protease calpain 3 has been reported to be responsible for cytosolic retention of CARP [12]. It appears that Ankrd1/CARP can function as prohypertrophic gene in the myofibril by gain of function and as an anti-hypertrophic gene in the nucleus by suppression of cardiac genes expression [11,13]. CARP is involved in calcium-dependent signaling [2], while increased binding of CARP to titin and myopalladin has been suggested to induce
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