Donate Help Contact The AHA Sign In Home
American Heart Association
Hypertension
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Hypertension. 2005;45:1182-1187
Published online before print May 16, 2005, doi: 10.1161/01.HYP.0000168051.04275.ea
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow Data Supplement
Right arrow All Versions of this Article:
45/6/1182    most recent
01.HYP.0000168051.04275.eav1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yaghini, F. A.
Right arrow Articles by Malik, K. U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yaghini, F. A.
Right arrow Articles by Malik, K. U.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Related Collections
Right arrow Lipids
Right arrow Remodeling
Right arrow Peripheral vascular disease
Right arrow Carotid Stenosis
Right arrow Other Research

(Hypertension. 2005;45:1182.)
© 2005 American Heart Association, Inc.

Original Articles

Contribution of Arachidonic Acid Metabolites Derived Via Cytochrome P4504A to Angiotensin II–Induced Neointimal Growth

Fariborz A. Yaghini; Chunxiang Zhang; Jean-Hugues Parmentier; Anne M. Estes; Nauzanene Jafari; Susan A. Schaefer; Kafait U. Malik

From the Department of Pharmacology and Center for Vascular Biology, University of Tennessee Health Science Center, Memphis, Tenn.

Correspondence to Kafait U. Malik, DSc, PhD, Department of Pharmacology, College of Medicine, 874 Union Avenue, University of Tennessee Health Science Center, Memphis, TN 38163. E-mail kmalik{at}utmem.edu


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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 balloon-injured 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 µmol/L) increased neointimal thickening at day 14 (intima/media ratio 0.71±0.14 with vehicle versus 1.65±0.10 with angiotensin II or 1.31±0.13 with arachidonic acid; P<0.05). Cytochrome P450 4A1 antisense, but not scrambled, oligodeoxynucleotide (100 nmol/L) reduced angiotensin II-induced or arachidonic acid-induced neointimal thickening (intima/media ratio 0.90±0.07 for angiotensin II and 0.95±0.06 for arachidonic acid). 20-hydroxyeicostetraenoic acid (0.5 µmol/L) also increased neointimal thickening of injured artery (intima/media ratio 1.15±0.03); 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 • arachidonic acids • balloon injury • cytochrome p450 • vascular smooth muscle


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Angiotensin 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 {kappa}B and activating protein-1) and pro-inflammatory 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 A2, which catalyzes the hydrolysis of phospholipids, leading to release of arachidonic acid (AA). AA is subsequently metabolized by cyclooxygenase (COX) into prostanoids, by lipoxygenase (LO) into 5(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acid (HETE), and by cytochrome P450 (CYP) into 18-HETE, 19-HETE, 20-HETE and epoxyeicosatrienoic acids.4–6 AA metabolites generated via LO [12(S)-HETE] and CYP4A (20-HETE) have been implicated in the vascular actions of Ang II. For example, 12(S)-HETE contributes to Ang II-induced VSMC hypertrophy and stimulates monocyte adhesion to endothelial cells.7–9 Moreover, there is increased expression of 12-LO in rat carotid artery after balloon injury, and 12-LO hammerhead ribozyme decreases VSMC fibronectin expression and migration as well as neointimal growth.8,10,11

20-HETE has multiple effects as well. It is a potent vasoconstrictor in small arteries and increases reactivity of the mesenteric arteries in spontaneously hypertensive rats.12,13 It also mediates the vasoconstrictor effect of Ang II and the mitogenic effect of norepinephrine and contributes to the development of hypertension.14–18 Overexpression of CYP4A1 in smooth muscle in renal arterial microvessels stimulates endothelial sprouting.19 The demonstration that: (1) Ang II promotes neointimal formation in balloon-injured rat carotid arteries20; (2) CYP4A and its activity is expressed in various tissues including the vasculature19,21; and (3) expression of CYP4A1 is increased in neointimal smooth muscle cells22 raises the possibility that CYP4A-derived metabolite(s) of AA contribute to the Ang II-induced increase in neointimal growth during vascular injury. To test this hypothesis, we examined the effects of CYP4A antisense and scrambled oligodeoxynucleotides (ODNs) on Ang II-induced neointimal growth as well as the effects of exogenous AA and 20-HETE in the presence or absence of these ODNs on neointimal growth in balloon-injured rat carotid arteries.


*    Materials and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Rabbit polyclonal CYP450 4A, purified mouse anti-rat CD45, and polyclonal actin antibodies were purchased from Novus Biologicals (Littleton, Colo), BD Biosciences (Palo Alto, Calif), and Santa Cruz Biotechnology, Inc (Santa Cruz, Calif), respectively. Antigen Unmasking Solution, Vectastain ABC kit, DAB kit, and Vectamount were purchased from Vector Laboratories, Inc (Burlingame, Calif).

Oligonucleotides
Phosphorothioate antisense ODN was designed from nucleotide 10 to 30 of rat CYP4A1 cDNA (GenBank, M14972). The scrambled ODN had the same nucleotide content as antisense, but in random order. CYP4A1 antisense ODN (5'-CAG-TGC-AGA-GAC-GCT-CATGGT-3') and scrambled ODN (5'-CTG-ACC-GCA-GCA-CTT-AGA-TGG-3') were synthesized (Integrated DNA Technologies, Inc, Coralville, Iowa) following the recommendations of Stein23–25 to minimize nonspecific effects in vivo. The CYP4A antisense ODN used did not share homology with any other known cDNA sequence. The effects of CYP4A1 antisense and scrambled ODN on CYP4A protein level were examined in rat aortic VSMC in vitro as described in the data supplement. Ang II, AA, or 20-HETE in saline alone or in combination with antisense or scrambled ODN mixed with oligofectamine reagent (Invitrogen, Carlsbad, Calif) was applied to balloon-injured rat carotid arteries as described.

Cell Culture and Transfection
VSMCs from male Sprague-Dawley rats were isolated, cultured, and maintained as described.26 VSMCs were transfected with CYP4A1 antisense or scrambled ODN with transfection reagent, oligofectamine (Invitrogen) according to manufacturer’s instruction. VSMCs were then lysed and used for Western blot analysis (available in the data supplement at http://www.hypertension.aha.org).

Vascular Injury Model, Vessel Preparation, Morphometric and Immunohistochemical Analyses
Treatment of the laboratory animals and the experimental protocols followed the guidelines of the University of Tennessee Health Science Center. Carotid artery balloon injury was performed as described.27 Briefly, 5 to 7 male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass) (200 to 250 grams) were intraperitoneally injected and anesthetized with ketamine (60 mg/kg) and xylazine (5 mg/kg) for each group of treatments, then the right common carotid artery was exposed, clamped, and injured with a 2-French Fogarty catheter. Drugs with or without CYP4A1 antisense or scrambled ODN were infused into the injured, clamped segment and incubated for 60 minutes. Exposure of rat injured carotid arteries for this or even shorter time period to phosphorothioate antisense ODN against growth factors has been reported to be effective in decreasing neointimal growth.24,28,29 After 60 minutes, the drugs and catheter were withdrawn, the external carotid artery was ligated, and blood flow was restored to the common carotid artery. The isolation and preparation of nonthrombotic arteries for morphometric and immunohistochemical analyses are described in the data supplement.

Western Blot Analysis
Three to 4 carotid arteries after 2 days from each treatment group were ground to a fine powder in liquid nitrogen (LN2). The lysates of these arteries or cultured VSMCs were prepared and subjected to Western blot analysis as described (data supplement).

Statistical Analysis
The results are presented as mean±SEM. The unpaired Student t test was used to determine the difference between 2 groups. P<0.05 was considered statistically significant.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Contribution of CYP4A to Ang II–Induced Neointimal Formation
CYP4A1 antisense but not scrambled ODN reduced CYP4A protein level in both cultured VSMCs and in vivo injured carotid arteries (Figure I, available at http://hyper.ahajournals.org). Balloon injury in rat carotid arteries caused neointimal growth as indicated by an increase in the ratio of intima to media (0.71±0.14 in vehicle-treated versus 0.12±0.02 in uninjured vessels; P<0.05, n=5). Exposure of injured carotid arteries to Ang II (200 nmol/L) for 60 minutes increased neointimal growth (Figure 1A and 1B); this short-term exposure to Ang II did not promote neointimal growth in the absence of balloon injury (data not shown). The effect of Ang II on neointimal growth was diminished in carotid arteries exposed to CYP4A1 antisense, but not scrambled, ODN (100 nmol/L; Figure 1A and 1B). The neointimal growth caused by injury alone was not altered by exposure to CYP4A1 antisense or scrambled ODN.



View larger version (64K):
[in this window]
[in a new window]
  		Figure 1. Effect of CYP4A1 antisense ODN on Ang II-induced neointimal formation. Sections of balloon-injured carotid artery were stained with H&E. A, Ang II (200 nmol/L) induced neointimal formation in carotid artery after injury compared with its vehicle (Veh). Treatment with CYP4A1 antisense (As), but not scrambled (Scr), ODN (100 nmol/L) diminished Ang II-induced intimal hyperplasia after injury. B, The bar graph shows the intima to media ratio (I/M) of carotid artery segments from 5 to 6 animals in each group. *Value different from the corresponding value obtained in the presence of vehicle and **value different from the corresponding value obtained in the presence of CYP4A1 scrambled ODN (P<0.05).

Contribution of CYP4A to AA-Induced Intimal Growth
To determine if exogenous AA mimics the action of Ang II and its effect is mediated through CYP4A, balloon-injured carotid arteries were incubated with AA (10 µmol/L) for 60 minutes. AA enhanced the neointimal growth in injured carotid artery (Figure 2A and 2B). Treatment with CYP4A1 antisense, but not scrambled, ODN attenuated the effect of AA on neointimal growth (Figure 2A and 2B).



View larger version (63K):
[in this window]
[in a new window]
  		Figure 2. Effect of CYP4A1 antisense ODN on AA-induced neointimal growth. Sections of carotid artery were stained with H&E. A, AA (10 µmol/L) enhanced intimal proliferation in injured rat carotid artery compared with its vehicle (Veh). CYP4A1 antisense but not scrambled ODN (100 nmol/L) decreased AA-induced neointimal formation in injured arteries. B, The bar graph denotes the intima to media ratio (I/M) in carotid artery segments from 5 to 6 animals in each group. *Value different from the corresponding value obtained in the presence of vehicle and **value different from the corresponding value obtained in the presence of CYP4A1 scrambled ODN (P<0.05).

Effect of 20-HETE on Neointimal Formation
To evaluate the effect of AA-derived CYP4A metabolite on intimal growth, balloon-injured carotid arteries were incubated with 20-HETE (0.5 µmol/L) for 60 minutes. 20-HETE increased the growth of neointima (Figure 3A and 3B). The increase in neointimal growth caused by 20-HETE was not altered by exposure of injured carotid arteries to CYP4A1 antisense or scrambled ODN (Figure 3A).



View larger version (65K):
[in this window]
[in a new window]
  		Figure 3. Effect of CYP4A1 antisense ODN on 20-HETE-induced neointimal growth. Sections of carotid artery were stained with H&E. A, 20-HETE (0.5 µmol/L) increased neointimal proliferation in injured carotid artery compared with its vehicle (Veh). Treatment with CYP4A1 antisense, as well as scrambled, ODN (100 nmol/L), did not attenuate 20-HETE–induced intimal hyperplasia after injury. B, The bar graph shows the intima to media ratio (I/M) in artery segments from 5 to 7 animals in each group. *Value different from the corresponding value obtained in the presence of vehicle (P<0.05).

Expression of Immunoreactive CYP4A in Injured Rat Carotid Artery
To determine expression of CYP4A, 0.5-µm sections of carotid arteries were immunostained with rabbit polyclonal CYP4A antibody as described in Materials and Methods. Exposure of balloon-injured carotid arteries to CYP4A1 antisense, but not scrambled, ODN attenuated the expression of CYP4A in arteries 14 days after treatment with Ang II, AA, or 20-HETE (Figure 4). Higher magnification of this Figure is shown in online Figure II (20x).



View larger version (105K):
[in this window]
[in a new window]
  		Figure 4. Expression of CYP4A in balloon-injured rat carotid artery. Sections of carotid artery from at least 5 animals in each group were immunostained with CYP4A antibody. Cross-sections of carotid artery were probed with polyclonal CYP4A antibody 14 days after injury. Ang II, AA, and 20-HETE induced neointimal growth was associated with an increased expression of CYP4A, as indicated by CYP4A immunostaining. The CYP4A expression in neointimal growth was diminished by exposure to CYP4A1 antisense (As) but not scrambled ODN in Ang II-treated, AA-treated, and 20-HETE–treated arteries. The top and bottom black lines in each image represent internal and external elastic lamina, respectively.

Expression of Immunoreactive CD45-Positive Cells in Neointima After Injury
Ang II plays an important role in vascular inflammation and atherosclerosis.1 Also, Ang II activates immune cells and production of inflammatory mediators.2 To determine the effect of CYP4A antisense ODN on the density of inflammatory cells in neointima, we immunostained arterial sections with antibody to CD45, a leukocyte-common antigen. Ang II-induced, AA-induced, and 20-HETE–induced neointimal growth was associated with an increase in CD45-positive cells in the neointima of injured artery segments after 14 days. Exposure of the carotid artery to CYP4A1 antisense, but not scrambled, ODN markedly reduced the density of CD45-positive leukocytes in neointima (Figure 5). Higher magnification of this Figure is shown in online Figure III (20x).



View larger version (103K):
[in this window]
[in a new window]
  		Figure 5. Presence of CD45-positive leukocytes in balloon-injured rat carotid artery. Sections of injured carotid artery from at least 5 animals in each group were immunostained with CD45 antibody. Cross-sections of carotid artery were probed with mouse CD45 antibody on day 14. Ang II-induced, AA-induced, and 20-HETE–induced increases in neointimal growth were associated with increased staining of CD45-positive cells. The number of CD45-positive cells was decreased by treatment of carotid arteries with CYP4A1 antisense ODN in vessels exposed to Ang II or AA, but not 20-HETE. The top and bottom black lines represent internal and external elastic lamina, respectively.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
This study, for the first time to our knowledge, demonstrates that a CYP4A-derived AA metabolite, most likely 20-HETE, contributes to the effect of Ang II on neointimal growth in vivo in balloon-injured rat carotid arteries. In the present study, exposure of carotid arteries to Ang II (200 nmol/L) for 60 minutes after balloon injury caused a marked increase in neointimal growth as indicated by increased intima-to-media ratio at day 14. This increase in neointimal growth was associated with enhanced expression of CYP4A in the neointima, which was reduced by treatment with CYP4A1 antisense, but not scrambled, ODN. These observations and our demonstration that treatment of injured arteries with CYP4A1 antisense, but not scrambled, ODN inhibited Ang II-induced increase in neointimal growth suggest involvement of CYP4A. Our finding that CYP4A1 antisense ODN did not alter the neointimal growth caused by injury alone indicates that the effect of Ang II to promote neointimal formation is caused by release of AA. Ang II promotes release of AA via activation of cytosolic phospholipase A2.30,31 Our novel observation that direct exposure of injured arteries to AA increased neointimal growth, which was inhibited by treatment with CYP4A1 antisense ODN, supports this view.

CYP4A1 is the most efficient {omega}-hydroxylase that catalyzes the oxygenation of AA to 20-HETE.32 20-HETE constricts small blood vessels, promotes endothelial sprouting in renal arterial microvessels, and exacerbates myocardial reperfusion injury.12,32,33 20-HETE also mediates the vasoconstrictor effect of Ang II in the kidney.14 Increased urinary excretion of 20-HETE has been reported to be associated with endothelial dysfunction.33,34 Our finding that exposure of balloon-injured carotid arteries to 20-HETE increased neointimal growth that was not altered by simultaneous exposure to CYP4A1 antisense ODN, suggests that 20-HETE contributes to the effect of Ang II and AA on neointimal growth. However, the contribution of other CYP4A-derived AA metabolites to the neointimal growth caused by Ang II and exogenous AA cannot be excluded. The effect of CYP4A1 antisense ODN to reduce AA-induced but not 20-HETE–induced increase in neointimal growth confirms its selectivity in reducing the effect of AA on neointimal growth.

Balloon injury of arteries has been shown to promote infiltration of leukocytes to the adventitia around the site of injury and increase production of cytokines and chemokines that contribute to neointimal growth.35,36 Ang II causes activation of immune cells and stimulates production of pro-inflammatory mediators that contribute to an increase in vascular permeability and infiltration of inflammatory cells, including leukocytes.2 Our finding that Ang II and AA increased the number of leukocytes as detected by CD45-positive cells in arteries exposed to CYP4A1 scrambled ODN suggests that the inflammatory mediators released from these cells also contribute to neointimal growth. Because treatment of injured arteries with CYP4A1 antisense ODN decreased the number of CD45-positive cells and reduced neointimal growth, CYP4A-derived metabolites, most likely 20-HETE, stimulate the inflammatory process initiated by mediators released from leukocytes and smooth muscle cells during injury and exposure to Ang II. Polymorphonuclear leukocytes also synthesize 20-HETE,37,38 which could also play an important role in the inflammatory process including increased adhesion of leukocytes to injured arteries and neointimal growth. The effect of CYP4A1 antisense ODN to reduce adventitial CYP4A levels and CD45-positive cells as indicated by immunostaining was not as marked as in neointima and media. This could be because of insignificant degree of transfection of adventitia with CYP4A1 antisense ODN because it was applied intraluminally for only 60 minutes. Moreover, we cannot exclude the possibility of involvement of other mediator(s) of leukocyte recruitment in this part of the vessel wall.

Ang II via generation of 20-HETE may promote neointimal growth by activating one or more mitogen-activated protein kinase, such as extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, JNK, or Akt.1,39 Both Ang II and 20-HETE increase the activity of one or more of these kinases in VSMCs, and inhibition of the activity of these kinases reduces neointimal growth caused by vascular injury.1,40–42 These kinases are also activated by reactive oxygen species generated by Ang II.3 A recent study has shown that reactive oxygen species produced by Ang II in adventitial fibroblasts and macrophages promote medial smooth muscle hypertrophy by paracrine action.43 Because AA has also been shown to stimulate production of reactive oxygen species in VSMCs,44 it is possible that the reactive oxygen species released by AA via activation of phospholipase A2 and/or are generated during AA metabolism by CYP4A in one or more cell types of the vessel wall, as well as other inflammatory cells, contribute to the action of Ang II on neointimal growth.

Perspectives
The present study demonstrates that a CYP4A-derived AA metabolite(s), most likely 20-HETE, contribute(s) to the effect of Ang II in stimulating neointimal growth in balloon-injured rat carotid arteries. Because the LO and COX pathways have also been implicated in neointimal formation during injury, the relative contribution of various AA metabolites to Ang II-induced neointimal formation need to be determined. Moreover, identifying the cell types that generate AA metabolites and elucidating their mechanisms of action should enhance our understanding of how Ang II and other growth factors stimulate neointimal formation. Finally, the information generated from these studies could illuminate novel targets for the development of therapeutic agents for the treatment of restenosis, atherosclerosis, and other vascular diseases.


*    Acknowledgments
 
We thank Dr Lauren M. Cagen for his editorial comments. This work has been supported by National Institutes of Health grant R01 HL79109-01 from the National Heart, Lung, and Blood Institute. Dr Fariborz A. Yaghini is the postdoctoral trainee supported by the National Institutes of Health training grant 2 T32HL07641 and by Neuroscience Center of Excellence, University of Tennessee Health Science Center. Nauzanene Jafari was a summer research student of the American Society of Pharmacology and Experimental Therapeutics.

Received January 27, 2005; first decision March 14, 2005; accepted April 18, 2005.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev. 2000; 52: 639–672.[Abstract/Free Full Text]
  2. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003; 35: 881–900.[CrossRef][Medline] [Order article via Infotrieve]
  3. Griendling KK, Sorescu D, Ushio-Fukai M. NADPH oxidase. Role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.[Abstract/Free Full Text]
  4. McGiff JC. Prostaglandins, prostacyclin, and thromboxanes. Annu Rev Pharmacol Toxicol. 1981; 21: 479–509.[CrossRef][Medline] [Order article via Infotrieve]
  5. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983; 220: 568–575.[Abstract/Free Full Text]
  6. Capdevila JH, Falck JR. Biochemical and molecular properties of the cytochrome P450 arachidonic acid monooxygenases. Prostaglandins Other Lipid Mediat. 2002; 68–69: 325–344.
  7. Stern N, Golub M, Nozawa K, Berger M, Knoll E, Yanagawa N, Natarajan R, Nadler JL, Tuck ML. Selective inhibition of angiotensin II-mediated vasoconstriction by lipoxygenase blockade. Am J Physiol. 1989; 257: H434–443.[Medline] [Order article via Infotrieve]
  8. Reddy MA, Thimmalapura PR, Lanting L, Nadler JL, Fatima S, Natarajan R. The oxidized lipid and lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid induces hypertrophy and fibronectin transcription in vascular smooth muscle cells via p38 MAPK and cAMP response element-binding protein activation. Mediation of angiotensin II effects. J Biol Chem. 2002; 277: 9920–9928.[Abstract/Free Full Text]
  9. Patricia MK, Kim JA, Harper CM, Shih PT, Berliner JA, Natarajan R, Nadler JL, Hedrick CC. Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 2615–2622.[Abstract/Free Full Text]
  10. Natarajan R, Pei H, Gu JL, Sarma JM, Nadler J. Evidence for 12-lipoxygenase induction in the vessel wall following balloon injury. Cardiovasc Res. 1999; 41: 489–499.[Abstract/Free Full Text]
  11. Gu JL, Pei H, Thomas L, Nadler JL, Rossi JJ, Lanting L, Natarajan R. Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries. Circulation. 2001; 103: 1446–1452.[Abstract/Free Full Text]
  12. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002; 82: 131–185.[Abstract/Free Full Text]
  13. Zhang F, Wang MH, Krishna UM, Falck JR, Laniado-Schwartzman M, Nasjletti A. Modulation by 20-HETE of phenylephrine-induced mesenteric artery contraction in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension. 2001; 38: 1311–1315.[Abstract/Free Full Text]
  14. Alonso-Galicia M, Maier KG, Greene AS, Cowley AW Jr, Roman RJ. Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II. Am J Physiol Regul Integr Comp Physiol. 2002; 283: R60–R68.[Abstract/Free Full Text]
  15. Uddin MR, Muthalif MM, Karzoun NA, Benter IF, Malik KU. Cytochrome P-450 metabolites mediate norepinephrine-induced mitogenic signaling. Hypertension. 1998; 31: 242–247.[Abstract/Free Full Text]
  16. Su P, Kaushal KM, Kroetz DL. Inhibition of renal arachidonic acid omega-hydroxylase activity with ABT reduces blood pressure in the SHR. Am J Physiol. 1998; 275: R426–R438.[Medline] [Order article via Infotrieve]
  17. Oyekan AO, McAward K, Conetta J, Rosenfeld L, McGiff JC. Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension. Am J Physiol. 1999; 276: R766–R775.[Medline] [Order article via Infotrieve]
  18. Muthalif MM, Karzoun NA, Gaber L, Khandekar Z, Benter IF, Saeed AE, Parmentier JH, Estes A, Malik KU. Angiotensin II-induced hypertension: contribution of Ras GTPase/Mitogen-activated protein kinase and cytochrome P450 metabolites. Hypertension. 2000; 36: 604–609.[Abstract/Free Full Text]
  19. Jiang M, Mezentsev A, Kemp R, Byun K, Falck JR, Miano JM, Nasjletti A, Abraham NG, Laniado-Schwartzman M. Smooth muscle–specific expression of CYP4A1 induces endothelial sprouting in renal arterial microvessels. Circ Res. 2004; 94: 167–174.[Abstract/Free Full Text]
  20. Bruijns RH, van Kleef EM, Smits JF, De Mey JG, Daemen MJ. Effects of chemical sympathectomy on angiotensin II-induced neointimal growth in the balloon-injured rat carotid artery. J Vasc Res. 1998; 35: 124–133.[CrossRef][Medline] [Order article via Infotrieve]
  21. Persohn E, Thomas H, Waechter F. Immunoelectron microscopic localization of cytochrome P-450 isoenzyme CYP4A1 in liver, ileum and kidney of nafenopin treated male rats. Cell Biol Int. 1993; 17: 99–103.[CrossRef][Medline] [Order article via Infotrieve]
  22. Giachelli CM, Majesky MW, Schwartz SM. Developmentally regulated cytochrome P-450IA1 expression in cultured rat vascular smooth muscle cells. J Biol Chem. 1991; 266: 3981–3986.[Abstract/Free Full Text]
  23. Stein CA. The experimental use of antisense oligonucleotides: a guide for the perplexed. J Clin Invest. 2001; 108: 641–684.[CrossRef][Medline] [Order article via Infotrieve]
  24. Rabbani LE, Wang W. Phosphorothioate oligodeoxynucleotide inhibition of restenosis. J Thromb Thrombolysis. 1998; 5: 125–128.[CrossRef][Medline] [Order article via Infotrieve]
  25. Wang MH, Guan H, Nguyen X, Zand BA, Nasjletti A, Laniado-Schwartzman M. Contribution of cytochrome P-450 4A1 and 4A2 to vascular 20-hydroxyeicosatetraenoic acid synthesis in rat kidneys. Am J Physiol. 1999; 276: F246–F253.[Medline] [Order article via Infotrieve]
  26. Fatima S, Yaghini FA, Ahmed A, Khandekar Z, Malik KU. CaM kinase IIalpha mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope. J Cell Sci. 2003; 116: 353–365.[Abstract/Free Full Text]
  27. Chen SJ, Li H, Durand J, Oparil S, Chen YF. Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation. 1996; 93: 577–584.[Abstract/Free Full Text]
  28. Morishita R, Gibbons GH, Tomita N, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. Antisense oligodeoxynucleotide inhibition of vascular angiotensin-converting enzyme expression attenuates neointimal formation: evidence for tissue angiotensin-converting enzyme function. Arterioscler Thromb Vasc Biol. 2000; 20: 915–922.[Abstract/Free Full Text]
  29. Agrotis A, Kanellakis P, Kostolias G, Di Vitto G, Wei C, Hannan R, Jennings G, Bobik A. Proliferation of neointimal smooth muscle cells after arterial injury. Dependence on interactions between fibroblast growth factor receptor-2 and fibroblast growth factor-9. J Biol Chem. 2004; 279: 42221–42229.[Abstract/Free Full Text]
  30. Rao GN, Lassegue B, Griendling KK, Alexander RW, Berk BC. Hydrogen peroxide-induced c-fos expression is mediated by arachidonic acid release: role of protein kinase C. Nucleic Acids Res. 1993; 21: 1259–1263.[Abstract/Free Full Text]
  31. Muthalif MM, Benter IF, Uddin MR, Harper JL, Malik KU. Signal transduction mechanisms involved in angiotensin-(1–7)-stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth muscle cells. J Pharmacol Exp Ther. 1998; 284: 388–398.[Abstract/Free Full Text]
  32. Nguyen X, Wang MH, Reddy KM, Falck JR, Schwartzman ML. Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors. Am J Physiol. 1999; 276: R1691–R1700.[Medline] [Order article via Infotrieve]
  33. Nithipatikom K, Gross ER, Endsley MP, Moore JM, Isbell MA, Falck JR, Campbell WB, Gross GJ. Inhibition of cytochrome P450{omega}-hydroxylase. A novel endogenous cardioprotective pathway. Circ Res. 2004; 95: e65–e71.[Abstract/Free Full Text]
  34. Ward NC, Rivera J, Hodgson JM, Beilin LJ, Croft KD. Urinary 20-hydroxyeicosatetraenoic acid is associated with endothelial dysfunction in humans. Circulation. 2004; 110: 438–443.[Abstract/Free Full Text]
  35. Okamoto E, Couse T, De Leon H, Vinten-Johansen J, Goodman RB, Scott NA, Wilcox JN. Perivascular inflammation after balloon angioplasty of porcine coronary arteries. Circulation. 2001; 104: 2228–2235.[Abstract/Free Full Text]
  36. Xing D, Miller A, Novak L, Rocha R, Chen YF, Oparil S. Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury. Circulation. 2004; 109: 234–241.[Abstract/Free Full Text]
  37. Hill E, Murphy RC. Quantitation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) produced by human polymorphonuclear leukocytes using electron capture ionization gas chromatography/mass spectrometry. Biol Mass Spectrom. 1992; 21: 249–253.[CrossRef][Medline] [Order article via Infotrieve]
  38. Rosolowsky M, Campbell WB. Synthesis of hydorxyeicosatetraenoic (HETEs) and epoxyeicosatrienoic acids (EETs) by cultured bovine coronary endothelial cells. Biochim Biophys Acta. 1996; 1299: 267–277.[Medline] [Order article via Infotrieve]
  39. Takahashi T, Taniguchi T, Konishi H, Kikkawa U, Ishikawa Y, Yokoyama M. Activation of Akt/protein kinase B after stimulation with angiotensin II in vascular smooth muscle cells. Am J Physiol. 1999; 276: H1927–H1934.[Medline] [Order article via Infotrieve]
  40. Muthalif MM, Benter IF, Karzoun N, Fatima S, Harper J, Uddin MR, Malik KU. 20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1998; 95: 12701–12706.[Abstract/Free Full Text]
  41. Kalyankrishna S, Malik KU. Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A(2) in vascular smooth muscle cells. J Pharmacol Exp Ther. 2003; 304: 761–772.[Abstract/Free Full Text]
  42. Kim S, Iwao H. Stress and vascular responses: mitogen-activated protein kinases and activator protein-1 as promising therapeutic targets of vascular remodeling. J Pharmacol Sci. 2003; 91: 177–181.[CrossRef][Medline] [Order article via Infotrieve]
  43. Liu J, Ormsby A, Oja-Tebbe N, Pagano PJ. Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circ Res. 2004; 95: 587–594.[Abstract/Free Full Text]
  44. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141–1148.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik
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, December 1, 2005; 289(6): H2592 - H2601.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow Data Supplement
Right arrow All Versions of this Article:
45/6/1182    most recent
01.HYP.0000168051.04275.eav1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yaghini, F. A.
Right arrow Articles by Malik, K. U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yaghini, F. A.
Right arrow Articles by Malik, K. U.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Related Collections
Right arrow Lipids
Right arrow Remodeling
Right arrow Peripheral vascular disease
Right arrow Carotid Stenosis
Right arrow Other Research

Hypertension Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2005 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.