title: Chronic blockade of class I PI3-kinase attenuates Ang II-induced cardiac hypertrophy and autophagic alteration.
abstract: 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.
  
  
  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.
authors: Department of Cardiovascular Surgery, Second Hospital of Jilin University, Jilin University, Changchun, Jilin, China. Chengwen.Sun@ndsu.edu.
authors: W
authors: W
authors: Yan
authors: L R
authors: LR
authors: Guo
authors: Q
authors: Q
authors: Zhang
authors: W-Z
authors: WZ
authors: Sun
authors: S T
authors: ST
authors: O'Rourke
authors: K-X
authors: KX
authors: Liu
authors: C-W
authors: CW
authors: Sun
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species