ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery.
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.
Li
Fang
F
Dept. of Pharmacology, Univ. of Tennessee Health Science Center, 874 Union Ave., Rm. 216 Crowe Bldg., Memphis, TN 38163, USA.
Zhang
Chunxiang
C
Schaefer
Susan
S
Estes
Anne
A
Malik
Kafait U
KU
D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology*; D002404:Catheterization / Q000009:adverse effects; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D008297:Male; D010739:Phospholipase D / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000804:Angiotensin II; D051057:Proto-Oncogene Proteins c-akt; D010741:Phospholipases A; D054467:Phospholipases A2; C105606:phospholipase D2; D010739:Phospholipase D