Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFκB activation in vivo

A role for the PI3K/Akt/mTOR pathway in cardiac hypertrophy has been well documented. We reported that NF kappa B activation is needed for cardiac hypertrophy in vivo. To investigate whether both NF kappa B activation and PI3K/Akt/mTOR signaling participate in the development of cardiac hypertrophy, two models of cardiac hypertropby, namely, induction in caAkt-transgenic mice and by aortic banding in mice, were employed. Rapamnycin (2 mg/kg/daily), an inhibitor of the mammalian target of rapamycin, and the antioxidant pyrrolidine dithiocarbamate (PDTC; 120 mg/kg/daily), which can inhibit NF kappa B activation, were administered to caAkt mice at 8 weeks of age for 2 weeks. Both rapamycin and PDTC were also administered to the mice immediately after aortic banding for 2 weeks. Administration of either rapamycin or PDTC separately or together to caAkt mice reduced the ratio of heart weight/body weight by 21.54, 32.68, and 42.07% compared with untreated caAkt mice. PDTC administration significantly reduced cardiac NF kappa B activation by 46.67% and rapamycin significantly decreased the levels of p70S6K by 34.20% compared with untreated caAkt mice. Similar results were observed in aortic-banding-induced cardiac hypertrophy in mice. Our results suggest that both NF kappa B activation and the PI3K/Akt signaling pathway participate in the development of cardiac hypertrophy in vivo. (c) 2005 Elsevier Inc. All rights reserved.