OBJECTIVE: Chronic Ang II stimulation is linked to cardiac remodeling characterized by fibrosis and cardiac hypertrophy. However, the underlying cellular mechanisms involved are not yet fully known. Here, we studied the molecular mechanisms underlying the chronic effect of Ang II on cardiac hypertrophy, fibrosis, and autophagy.
MATERIALS AND METHODS: The role of class I PI3-kinase in these actions of Ang II was studied using lentiviral vector-mediated expression of a dominant negative form of PI3-kinase subunit p85α (Lv-DNp85) in the heart. Ang II was infused subcutaneously for 4 weeks on rats using osmotic pumps. Cardiac hypertrophy, fibrosis, reactive oxygen species (ROS), and autophagy were examined in four groups of rats (Ang II+Lv-DNp85, Ang II+Lv-GFP, Saline+Lv-DNp85, Saline+Lv-GFP).
RESULTS: Chronic infusion of Ang II induced severe cardiac hypertrophy and perivascular fibrosis in the heart. These effects were associated with a significant reduction in LC3 II and elevation in ROS levels, suggesting marked impairment of cardiac autophagy and increased generation of ROS. Cardiac transduction of Lv-DNp85 significantly attenuated Ang II-induced impairment of autophagy and elevation of ROS, as well as Ang II-induced cardiac hypertrophy and perivascular fibrosis. To study the cellular mechanisms underlying those actions of Ang II, phosphorylated Akt and mTOR were measured in hearts from these rats. Ang II increased phosphorylation of Akt and mTOR; and cardiac transduction of Lv-DNp85 significantly abolished Ang II-induced phosphorylation of Akt and mTOR, a signaling pathway inhibiting autophagy.
CONCLUSIONS: These results demonstrate that class I PI3-kinase, via activation of the Akt-mTOR pathway, is involved in Ang II-induced impairment of autophagy, elevation of ROS, cardiac hypertrophy, and fibrosis, suggesting a novel target for cardiac protection.Free PDF Download
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To cite this article
W. Yan, L.R. Guo, Q. Zhang, W.-Z. Sun, S.T. O’Rourke, K.-X. Liu, C.-W. Sun
Chronic blockade of class I PI3-kinase attenuates Ang II-induced cardiac hypertrophy and autophagic alteration
Eur Rev Med Pharmacol Sci
Vol. 19 - N. 5