Abstract-Angiotensin II and the arachidonic acid metabolite derived via cytochrome P450 20-hydroxyeicostetraenoic acid promote vasoconstriction and vascular smooth muscle cell (VSMC) proliferation. This study was conducted to determine if 20-hydroxyeicostetraenoic acid contributes to angiotensin II-induced neointimal formation in ballooninjured rat carotid artery. In anesthetized rats, the drugs were infused into the clamped segment of the injured right common carotid artery for 60 minutes. The drug solution and catheter were withdrawn, the common carotid artery was ligated, and blood flow was restored. Exposure of the injured artery to angiotensin II (200 nmol/L) or arachidonic acid (10 mol/L) increased neointimal thickening at day 14 (intima/media ratio 0.71Ϯ0.14 with vehicle versus 1.65Ϯ0.10 with angiotensin II or 1.31Ϯ0.13 with arachidonic acid; PϽ0.05). Cytochrome P450 4A1 antisense, but not scrambled, oligodeoxynucleotide (100 nmol/L) reduced angiotensin II-induced or arachidonic acid-induced neointimal thickening (intima/media ratio 0.90Ϯ0.07 for angiotensin II and 0.95Ϯ0.06 for arachidonic acid). 20-hydroxyeicostetraenoic acid (0.5 mol/L) also increased neointimal thickening of injured artery (intima/media ratio 1.15Ϯ0.03); this was not altered by cytochrome P450 4A1 antisense oligodeoxynucleotide. Angiotensin II, arachidonic acid, and 20-hydroxyeicostetraenoic acid also induced the expression of cytochrome P450 4A and increased the number of CD45-positive cells; the latter effect of angiotensin II and arachidonic acid, but not 20-hydroxyeicostetraenoic acid, was diminished by cytochrome P450 4A1 antisense oligodeoxynucleotide. These data suggest that arachidonic acid metabolites derived via cytochrome P450 4A, most likely 20-hydroxyeicostetraenoic acid, mediate angiotensin II-induced neointimal thickening in injured rat carotid artery. Key Words: angiotensin II Ⅲ arachidonic acids Ⅲ balloon injury Ⅲ cytochrome p450 Ⅲ vascular smooth muscle A ngiotensin II (Ang II), a biologically active octapeptide generated by the renin-angiotensin system, contributes to the regulation of blood pressure by maintaining vascular tone and salt and water balance. High levels of Ang II promote vascular smooth muscle cell (VSMC) hypertrophy, migration, and delayed hyperplasia, and cause inflammation, neointimal formation, and hypertension. 1,2 Growth factors such as Ang II promote activation of transcription factors (nuclear factor B and activating protein-1) and proinflammatory genes (cytokines, interleukins), upregulation of adhesion molecules (intercellular adhesion molecule, vascular cell adhesion molecule), stimulation of chemokine production (monocyte chemoattractant protein-1), and their receptors, and recruitment of inflammatory cells (monocytes, macrophages), all of which are critical processes involved in vascular inflammation and injury. 2,3 Ang II also activates cytosolic phospholipase A 2 , which catalyzes the hydrolysis of phospholipids, leading to release of arachidonic acid (AA). AA is subsequently metabolize...
. ANG II-induced neointimal growth is mediated via cPLA2-and PLD2-activated Akt in balloon-injured rat carotid artery. Am J Physiol Heart Circ Physiol 289: H2592-H2601, 2005. First published July 15, 2005; doi:10.1152/ajpheart.00450.2005.-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 A 2 (cPLA2)-dependent phospholipase D2 (PLD2). This study was conducted to determine whether ANG IIinduced neointimal thickening is mediated via cPLA 2-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 Ϯ 0.31 to 1.44 Ϯ 0.14, P Ͻ 0.01) or a retrovirus containing cPLA 2 small interfering RNA (siRNA; intima-to-media ratio from 3.01 Ϯ 0.31 to 1.16 Ϯ 0.36, P Ͻ 0.001) or PLD2 siRNA (intima-to-media ratio from 3.01 Ϯ 0.31 to 1.33 Ϯ 0.11, P Ͻ 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 CAROTID AND CORONARY ARTERY DISEASE, including stenosis (narrowing), restenosis, and atherosclerosis, occurs when the artery becomes injured (15,38). During these disease states, the injured arteries become so severely narrowed that the blood supply to the brain and heart is compromised. Atherosclerosis is the major cause of myocardial infarction, strokes, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries (15,38). Therefore, a thorough understanding of the regulatory networks involved in the pathological processes that occur during carotid and coronary artery disease may aid in the development of novel drugs and gene therapy strategies to treat cardiovascular diseases.The major pathophysiological process that is common to carotid artery stenosis and other vascular diseases involves injury of the endothelium and proliferation, migration, and accumulation of smooth muscle cells in the intima (37). Acute arterial injury promotes vascular smooth muscle cell (VSMC) proliferation and...
The contribution of atypical protein kinase C (PKC)-zeta to ANG II-accelerated restenosis after endoluminal vascular injury was investigated by using the rat carotid balloon injury model. Exposure of injured arteries to ANG II resulted in an extensive neointimal thickening (1.9 times) compared with vehicle at day 14. Treatment with PKC-zeta antisense, but not scrambled, oligonucleotides reduced neointimal formation observed in the presence or absence of ANG II. Examination of early events (2 days) after injury showed an increase in cellularity in the perivascular area of the artery wall that was transferred to the adventitia and media after exposure to ANG II, events blocked by PKC-zeta antisense, but not scrambled, oligonucleotides. A positive correlation between medial cellularity at day 2 and extent of neointimal growth at day 14 was established. Immunohistochemical analysis showed that upregulation of inflammatory markers after injury, as well as infiltration of ED1(+) monocytes/macrophages from the perivascular area to the adventitia, was accelerated by ANG II. However, ANG II-stimulated medial increase in cellularity was proliferation independent, and these cells were monocyte chemoattractant protein-1(+)/vimentin(+) but ED1(-)/VCAM(-). PKC-zeta is degraded after injury, and inhibition of its neosynthesis in medial vascular smooth muscle cells or in infiltrating cells with PKC-zeta antisense attenuated medial cellularity and expression of inflammation mediators without reversing smooth muscle cell dedifferentiation. Together, these data indicate that PKC-zeta plays a critical role in normal and ANG II-accelerated neointimal growth through a mechanism involving upregulation of inflammatory mediators, leading to cell infiltration in the media of the vascular wall.
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