Abstract 178: Calsarcin-1 Transgenic Mice are Resistant Against Angiotensin-II Induced Cardiac Hypertrophy
We have previously shown that deficiency for the sarcomeric z-disc protein calsarcin-1 (Calcineurin-interacting sarcomeric protein 1, CS1) sensitizes the heart to hypertrophic stimuli. We now hypothesized that CS1 might exhibit an antihypertrophic effect and therefore established transgenic mouse lines with cardiac-specific overexpression of CS1. CS1 was overexpressed 2.4-fold on the protein level and was orthotopically localized to the z-disc. Unstressed CS1-tg mice did not show an overt phenotype and displayed regular cardiac dimensions and normal contractile function. Likewise, analysis of cardiac gene expression, including ANF and β-MHC levels, revealed no difference compared to wildtype. When subjected to chronic infusion of Angiotensin-II (Ang-II, 14 days, 500 ng/kg/min), both CS1-tg and wildtype mice developed hypertension to a similar degree (WT: 145.0 mmHg, sem 6.9, n=6; CS1-tg: 148.9 mmHg, sem 5.2, n=10, p=0.67). However, in contrast to wildtype mice, Ang-II-treated CS1-tg animals did not show cardiac hypertrophy: LV/tibia length ratio was 6.9 mg/mm (sem 0.24) compared to 6.3 mg/mm (sem 0.63) in CS1 sham mice (n=6, p=0.4), while wildtype Ang-II mice displayed a ratio of 8.1 mg/mm (sem 0.22, n=6, p=0,004). Invasive hemody-namics revealed a comparable dP/dt max in CS1-tg and wildtype Ang-II-treated mice (10296 mmHg/s, sem 1233 vs. 10936, sem 990, p=0.72). On the molecular level, CS1-Tg mice showed a blunted induction of the hypertrophic gene program (ANF: WT Ang-II 4.9-fold, sem 0.1 vs. CS1-Tg Ang-II 1.5-fold, sem 0.1, p<0.0001; β-MHC: 10.1-fold, sem 0.8, vs. 2.2-fold, sem 0.4, p=0.004). The induction of the calcineurin-dependent gene MCIP-1 was also significantly reduced in CS-1-Tg mice (5.6-fold, sem 0.1 vs. 3.4-fold, sem 0.4, p=0.02), consistent with an inhibitory role of calsarcin-1 on calcineurin activity. No significant differences in the phosphorylation status of GSK3β, PKB or ERK1/2 were observed. In summary, we established a new transgenic mouse model with cardiac-restricted overexpression of calsarcin-1. Upon chronic Ang-II infusion, these mice lack a hypertrophic response, yet display preserved contractile function, suggesting that overexpression of calsarcin-1 may favorably modulate cardiac remodeling in vivo.