Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy.

BACKGROUND:We have previously shown that deficiency for the z-disc protein calsarcin-1 (CS1) sensitizes the heart to calcineurin signaling and to stimuli of pathological hypertrophy. In the present study we asked whether overexpression of CS1 might exhibit antihypertrophic effects, and therefore we tested this hypothesis both in vitro and in vivo. METHODS AND RESULTS:Adenoviral gene transfer of CS1 into neonatal cardiomyocytes inhibited hypertrophy as a result of Gq-agonist stimulation, including angiotensin-II (Ang-II), endothelin-1, and phenylephrine. Consistently, Adenoviral gene transfer of CS1 also led to the reduction of increased levels of atrial natriuretic factor (mRNA) and the calcineurin-sensitive gene MCIP1.4, suggesting that CS1 inhibits calcineurin-dependent signaling. Furthermore, we generated CS1-overexpressing transgenic mice (CS1Tg). Unchallenged CS1Tg mice did not exhibit a pathological phenotype as assessed by echocardiography and analysis of cardiac gene expression. Likewise, when subjected to long-term infusion of Ang-II, both CS1Tg and wild-type mice developed a similar degree of arterial hypertension. Yet, in contrast to wild-type mice, Ang-II-treated CS1Tg animals did not display cardiac hypertrophy. Despite the absence of hypertrophy, both fractional shortening and dP/dt(max) were preserved in CS1Tg Ang-II-treated mice as assessed by echocardiography and cardiac catheterization, respectively. Moreover, induction of the hypertrophic gene program (atrial natriuretic factor, brain natriuretic peptide) was markedly blunted, and expression of the calcineurin-dependent gene MCIP1.4 was significantly reduced in CS1Tg mice, again consistent with an inhibitory role of CS1 on calcineurin. CONCLUSIONS:The sarcomeric protein CS1 prevents Ang-II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling. Thus, overexpression of CS1 might represent a novel approach to attenuate pathological cardiac hypertrophy.

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