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ANG II-induced neointimal growth is mediated via cPLA₂- and PLD₂-activated Akt in balloon-injured rat carotid artery

¹Department of Pharmacology and ²Vascular Biology Center, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 3 May 2005 ; accepted in final form 12 July 2005

Angiotensin II (ANG II) promotes neointimal growth in the balloon-injured rat carotid artery. However, the mechanism by which ANG II stimulates neointimal growth during vascular injury is not known. In cultured vascular smooth muscle cells, ANG II activates Akt through cytosolic phospholipase A₂ (cPLA₂)-dependent phospholipase D₂ (PLD₂). This study was conducted to determine whether ANG II-induced neointimal thickening is mediated via cPLA₂- and PLD₂-activated Akt in balloon-injured rat carotid arteries. ANG II-stimulated neointimal growth was inhibited by exposure of the injured carotid arteries to an adenovirus containing a dominant negative Akt mutant (intima-to-media ratio from 3.01 ± 0.31 to 1.44 ± 0.14, P < 0.01) or a retrovirus containing cPLA₂ small interfering RNA (siRNA; intima-to-media ratio from 3.01 ± 0.31 to 1.16 ± 0.36, P < 0.001) or PLD₂ siRNA (intima-to-media ratio from 3.01 ± 0.31 to 1.33 ± 0.11, P < 0.001). The effect of cPLA₂ and PLD₂ siRNA to reduce the ANG II-induced increase in neointimal thickening was associated with reduced expression of cPLA₂ and PLD₂ as determined by immunohistochemical analysis in injured carotid arteries. Western blot analysis showed that Akt phosphorylation that was increased by ANG II was inhibited in injured carotid arteries 2 days after exposure to cPLA₂ or PLD₂ siRNA or in injured arteries isolated after exposure to these agents for 30 min and then placed in tissue culture media for 24 h in the presence of these agents. These data suggest that the ANG II-induced neointimal growth is mediated by the activation of Akt through a mechanism dependent on cPLA₂ and PLD₂ activation in balloon-injured rat carotid arteries.

angiotensin II; cytosolic phospholipase A₂; phospholipase D₂; vascular smooth muscle cells

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