(Hypertension. 2000;36:604.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin II–Induced Hypertension
Contribution of Ras GTPase/Mitogen-Activated Protein Kinase and Cytochrome P450 Metabolites
From the Departments of Pharmacology (M.M.M., N.A.K., Z.K, A.E.S., J.-H.P., A.E., K.U.M.) and Pathology (L.G.), University of Tennessee, Memphis; and Division of Biomedical Sciences (I.F.B.), Southern College of Optometry, Memphis, Tenn.
Correspondence to Dr Kafait U. Malik, Department of Pharmacology, College of Medicine, The University of Tennessee, 874 Union Ave, Memphis, TN 38163. E-mail kmalik{at}utmem1.utmem.edu
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Abstract—We reported that norepinephrine and angiotensin II (Ang II) activate the Ras/mitogen-activated protein (MAP) kinase pathway primarily through the generation of cytochrome P450 (CYP450) metabolites. The purpose of the present study was to determine the contribution of Ras and CYP450 to Ang II–dependent hypertension in rats. Infusion of Ang II (350 ng/min for 6 days) elevated mean arterial blood pressure (MABP) (171±3 mm Hg for Ang II versus 94±5 for vehicle group, P<0.05). Ras is activated on farnesylation by farnesyl protein transferase (FPT). When Ang II was infused in combination with FPT inhibitor FPT III (232 ng/min) or BMS-191563 (578 ng/min), the development of hypertension was attenuated (171±3 mm Hg for Ang II plus vehicle versus 134±5 mm Hg for Ang II plus FPT III and 116±6 mm Hg for Ang II plus BMS-191563, P<0.05). Treatment with the MAP kinase kinase inhibitor PD-98059 (5 mg SC) reduced MABP. The CYP450 inhibitor aminobenzotriazole (50 mg/kg) also diminished the development of Ang II–induced hypertension to 113±8 mm Hg. The activities of Ras, MAP kinase, and CYP450 measured in the kidney were elevated in hypertensive animals. The infusion of FPT III, BMS-191563, or aminobenzotriazole reduced the elevation in Ras and MAP kinase activity. Morphological studies of the kidney showed that FPT III treatment ameliorated the arterial injury, vascular lesions, fibrinoid necrosis, focal hemorrhage, and hypertrophy of muscle walls observed in hypertensive animals. These data suggest that the activation of Ras and CYP450 contributes to the development of Ang II–dependent hypertension and associated vascular pathology.
Key Words: angiotensin II • Ras • kinases • hypertension, experimental • cytochrome P450 • kidney
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Introduction |
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Angiotensin II (Ang II), the major biologically active component of the renin-angiotensin system, contributes to the regulation of vascular tone, salt and water balance, and blood pressure.1 2 It promotes vascular smooth muscle cell (VSMC) migration, hypertrophy, and delayed hyperplasia.3 4 5 Ang II also stimulates NADPH oxidase, p21 Ras, and phospholipase (PL)A2, PLC, and PLD.6 7 8 9 The activation of PLA2 and PLD by Ang II leads to the release of arachidonic acid,9 10 11 which is metabolized by cyclooxygenase to prostaglandins and thromboxane A2 and by lipoxygenase to hydroperoxyeicosatetraenoic acid (HPETE) and hydroxyeicosatetraenoic acid (HETE). The cyclooxygenase products prostaglandin (PG)E2 and PGI2 attenuate the vascular and renal actions of Ang II and contribute to the antihypertensive mechanisms.12 On the other hand, the cyclooxygenase product thromboxane A2 and the lipoxygenase product 12-HPETE, which inhibits PGI2 synthase and thereby promotes the vasoconstrictor effect of endoperoxide PGH2, contribute to the prohypertensive mechanisms.13 The level of blood pressure appears to be determined by the balance between the antihypertensive and prohypertensive eicosanoids.13 Recently, it was reported that Ang II also promotes the metabolism of arachidonic acid into 20-HETE, which constricts blood vessels, causes VSMC hyperplasia, and contributes to high blood pressure.14 15 16 17 Moreover, it has been reported that 20-HETE stimulates Ras-GTPase (Ras) and mitogen-activated protein (MAP) kinase activity, which mediates VSMC proliferation.18 19 These observations and the demonstrations that Ang II stimulates the Ras/MAP kinase pathway8 18 and that MAP kinase is involved in Ang II–induced VSMC contraction20 21 raise the possibility that Ras/MAP kinase activated by the cytochrome P450 (CYP450) product of arachidonic acid, 20-HETE, contributes to hypertension, vascular injury, and hypertrophy in Ang II–dependent models of hypertension. To test this hypothesis, we investigated the activity of Ras, MAP kinase, and CYP450 and the effect of their inhibition on hypertension and associated renal vascular injury and structural alterations produced by Ang II.
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Methods |
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Ang II was obtained from Bachem. Sodium pentobarbital, lauric acid, NAD, NADP, and heparin were from Sigma Chemical Co. The protein farnesyl transferase (FPT) inhibitors FPT III and BMS-191563 were from Calbiochem and a gift from Bristol-Myers Squibb, respectively. The osmotic minipump was from Alzet Corp. H-Ras antibody and anti-goat IgG were from Santa Cruz Biotechnology. Anti–glutathione S-transferase (GST) antibody was from Pharmacia Biotech and aminobenzotriazole (ABT) was from Acros. PD-98059, MAP kinase, and phosphospecific MAP kinase antibodies were from New England Biolabs. [14C]Lauric acid (55 mCi/mmol) was from Amersham.
Ang II–Induced Hypertension
All procedures were carried out in male Sprague-Dawley rats
(Charles River Laboratories), weighing 300 to 350 g, in accordance
with institutional guidelines for animal research. Ang II was infused
with an Alzet osmotic minipump as described previously22 .
Briefly, the animals were anesthetized with a
ketamine-xylazine mixture (80 mg/kg ketamine, 8 mg/kg
xylazine), a 1-cm midline incision was made in the abdominal cavity,
and an osmotic minipump filled with Ang II dissolved in 0.001N acetic
acid was inserted. Ang II was infused at a rate of 350 ng/min for 6
days. The sham control rats received 0.001N acetic acid, the vehicle of
Ang II. Inhibitors of Ras farnesyl transferase (2 mg FPT
III and 5 mg BMS-191563) were infused along with Ang II. The osmotic
minipump delivered FPT III (232 ng/min) or BMS-191563 (578 ng/min)
during a period of 6 days. The effect of the CYP450
inhibitor ABT (50 mg/kg) was evaluated by administering ABT
intraperitoneally every second day for 6 days.
The MAP kinase kinase (MEK) inhibitor PD-98059 (5 mg dissolved in 300 µL DMSO) or its vehicle was administered subcutaneously on the sixth day after Ang II infusion. Mean arterial blood pressure (MABP; expressed in mm Hg) was measured via a catheter inserted in the femoral artery in animals anesthetized with pentobarbital sodium (60 mg/kg IP). Blood pressure was measured with a pressure transducer (Grass Instruments) and recorded on a polygraph (Grass Instruments).
Measurement of Ras, MAP Kinase, and Phosphospecific MAP Kinase
Levels
Frozen kidney tissues were processed for Western blotting
analysis as described previously.23 Proteins (200
to 400 µg) were resolved by SDS-PAGE (12%) and Western blotted with
MAP kinase (1:1000 dilution) or Ras (1:200 dilution) or phosphospecific
MAP kinase (1:1000 dilution) antibodies. The blots were developed with
ECL Western blotting detection reagents (Amersham).
Measurement of Ras Activity
The Ras binding domain (RBD) of Raf-1, immobilized
by fusion to GST and bound to glutathione beads, was used as an
affinity reagent to precipitate Ras-GTP from cell
lysates.24 25 The procedures for GST-RBD preparation and
affinity precipitation of Ras-GTP were previously
described23 with a few modifications. Two milligrams of
proteins isolated from kidney tissues was incubated with GST-RBD bound
to 75 µL glutathione-Sepharose beads. The beads were then washed 3
times with buffer (25 mmol/L HEPES, pH 7.5, 150 mmol/L NaCl,
1% Nonidet P-40, 10% glycerol, 0.25% sodium deoxycholate, 25
mmol/L sodium fluoride, 10 mmol/L
MgCl2, 1 mmol/L EDTA, 1 mmol/L sodium
vanadate, 2 mmol/L PMSF, 10 µg/mL leupeptin, and 10 µg/mL
aprotinin), and bound proteins were resolved by SDS-PAGE and Western
blotted with H-Ras-235 monoclonal antibody.
CYP450 4A Activity
CYP450 4A activity, measured as lauric acid 12-hydroxylase
activity, was measured in kidney proteins according to a method
described previously.23
Histological Examination
The kidneys removed from the Ang II–induced hypertensive rats
with or without treatment with FPT III or ABT were sectioned and
processed as previously described.23 Semiquantitative
assessment of the severity and extent of the arterial
lesions was performed. The number and size of arteries affected per
cross section were determined. The affected arteries were examined for
fibrinoid necrosis, alterations in the endothelial or
smooth muscle cells, hemorrhage in the media, and concentric
mural hypertrophy.
Statistical Analysis
Values are reported as mean±SEM. The data were analyzed
by 1-way ANOVA, and the difference between the mean values for multiple
comparisons was determined with the Newman-Keuls test; a value of
P<0.05 was considered statistically significant.
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Results |
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Effects of Inhibitors of Ras Farnesyl Transferase and CYP450 on MABP in Rats With Ang II–Induced Hypertension
The blood pressure, measured as MABP, was significantly higher in rats infused with Ang II (171±3 mm Hg) than in those infused with vehicle (95±5 mm Hg; P<0.05; Figure 1). Body weight was reduced in rats after Ang II infusion (60±14 g). As previously reported,22 failure of the rats infused with Ang II to gain weight was associated with a reduction in the food intake, reduced sodium and potassium, and elevation in urinary volume (data not shown).
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Significantly
different from animals infused with Ang II alone (Veh)
(P<0.05).Infusion of Ras inhibitors FPT III and BMS-191563 with Ang II significantly reduced MABP (Figure 1). The decrease in body weight produced by Ang II infusion was not altered by the administration of FPT III and BMS-191563. The infusion of FPT III or BMS-191563 alone did not alter either MABP or body weight (data not shown). The MEK inhibitor PD-98059, when administered subcutaneously, reduced the blood pressure from 160 to 120 mm Hg within 30 to 60 minutes (n=4); blood pressure stayed at 120 mm Hg for an additional 30 minutes (Figure 2). The administration of DMSO (vehicle of PD-98059) did not alter the MABP in animals with Ang II–induced hypertension (data not shown). The administration of the CYP450 inhibitor ABT, which is known to reduce CYP450 activity in spontaneously hypertensive rats, also significantly reduced MABP in animals infused with Ang II. The administration of ABT alone did not alter MABP (Figure 3).
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CYP450 4A activity, measured as lauric acid hydroxylase activity, was elevated in the kidney of rats with Ang II–induced hypertension, and treatment with ABT attenuated this response (Figure 4). However, the administration of FPT III or BMS-191563, which are Ras farnesyl transferase inhibitors, did not alter the elevated levels of CYP450 activity in rats with Ang II–induced hypertension.
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Effects of Inhibitors of Ras Farnesyl Transferase and
CYP450 on Activation of Ras, MAP Kinase, and CYP450 in Rats With
Ang II–Induced Hypertension
Protein extracts were obtained from the kidneys of rats with Ang
II–induced hypertension, vehicle control animals, and hypertensive
animals treated with inhibitors of Ras, MEK, and CYP450.
Ras protein levels did not appear to be altered by the infusion of Ang
II. Moreover, neither FPT III, BMS-191563, nor ABT altered Ras protein
levels in the kidney of rats with Ang II–induced hypertension (Figure 5). Ras interacts with Raf and
activates the MEK/MAP kinase signaling pathway. Moreover, it
has been shown that residues 51 to 131 of mammalian Raf-1 (called the
RBD) bind activated Ras or Ras-GTP but not
Ras-GDP.26 27 The Ras activity, measured as Ras-GTP bound
to the RBD of Raf, was increased in the Ang II–infused hypertensive
rats (Figure 5). However, treatment of Ang II–induced
hypertensive animals with FPT III, BMS-191563, or ABT reduced Ras
activity in the kidneys (Figure 5). Treatment of normotensive
rats with these inhibitors did not alter Ras protein and
activity levels (data not shown).
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Western blot analysis with the MAP kinase antibody showed that similar levels of ERK1 and ERK2 were present in kidney extracts from normotensive and Ang II–induced hypertensive animals. Moreover, treatment of hypertensive animals with inhibitors of Ras farnesyl transferase and CYP450 did not alter the protein levels (Figure 5). However, phosphorylated MAP kinase levels were elevated with Ang II treatment. This MAP kinase activity was attenuated in the kidneys of hypertensive animals treated with FPT III, BMS-191563, or ABT (Figure 5).
Effects of Ras Farnesyl Transferase and CYP450
Inhibitors on the Morphological Changes in the Kidney of
Rats With Ang II–Induced Hypertension
Histological examination of the kidney sections
was performed with light microscopy and observed only vascular, not
glomerular, injury. There were no structural alterations in
animals infused with the vehicle of Ang II or FPT III in normotensive
untreated animals. Five animals made hypertensive with the infusion of
Ang II showed considerable hypertension-induced vascular pathology in
the form of concentric mural hypertrophy and the resultant
narrowing of the intrarenal arteries and in "onion-skin" changes in
the small arteries. A small branch of an interlobular artery displays
transmural fibrinoid necrosis and endothelial cell
hypertrophy (Figure 6A, arrow). The large interlobular artery shows hypertrophy of
the myocytes and a few red blood cells within the wall. Focal fibrinoid
necrosis was also apparent in other arteries of larger size. In
addition, four of the five kidneys showed hemorrhage in the
arteries, and 3 had fibrinoid necrosis. These lesions were widely
distributed in that they were apparent in the large and small
intrarenal arteries as well as in the extrarenal arteries located at
the hilum of the kidney. Fibrinoid necrosis was found in 2 to 10
arteries per renal cross section (Figure 6).
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On the other hand, 2 of 4 animals infused with Ang II plus FPT III had normal kidneys, as seen with light microscopy. Renal lesions in the other 2 animals were graded as mild and limited in terms of severity and the number of arteries with pathological lesions. A very mild and focal fibrinoid necrosis was detected in very few small arteries in these 2 kidneys (2 to 4 arteries with fibrinoid necrosis per cross section of the kidney). The interlobular artery at the cross section is essentially unremarkable except for the mild hypertrophy of the myocytes in the media of a few arteries (Figure 6).
Kidneys from 2 animals treated with Ang II plus ABT were also examined. Vascular lesions in both animals were limited and of mild intensity. One kidney showed focal hemorrhage in the wall of a single extrarenal artery, whereas the second kidney displayed circumferential fibrinoid degeneration in 1 small interlobular renal artery (data not shown).
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Discussion |
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The vascular and renal actions of Ang II play an important role in its hypertensive mechanism. The cardiovascular and renal actions of Ang II are mediated through 1 or more intracellular signaling molecules.1 2 3 6 7 For example, arachidonic acid metabolites generated through lipoxygenase (12-HETE) or CYP450 (20-HETE) pathways have been reported to contribute to the vascular actions of Ang II.28 29 These products of arachidonic acid may exert their effects through activation of the Ras/MAP kinase pathway in the cardiovascular system.18 30 31 The present study demonstrates that the development of Ang II–induced hypertension in rats is mediated in part via activation of Ras/MAP kinase, probably via generation of arachidonic acid metabolites through CYP450, most likely 20-HETE.
The intraperitoneal infusion of Ang II (125 to 200
ng/min) during a period of 11 days has been shown to increase
systolic blood pressure by 
55 mm Hg in
rats.22 However, in the present study, the infusion of
Ang II at 350 ng/min during a period of 6 days increased MABP by 60 to
80 mm Hg. The increase in MABP produced by Ang II infusion was
associated with an increase in Ras, MAP kinase, and CYP450 activities
in the kidney. That Ras contributes to this model of hypertension was
suggested by our demonstration that inhibitors of Ras
farnesylation, which reduce the association of Ras with membranes and
thereby its activity, significantly reduced MABP in animals infused
with Ang II. The mechanism by which Ras activation leads to Ang
II–induced hypertension most likely involves activation of the MEK/MAP
kinase pathway. Ang II has been reported to increase MAP kinase
activity through both Ras-dependent and Ras-independent
pathways.18 32 33 Our finding that the Ras
inhibitor FPT III decreased MAP kinase activity in the
kidney of Ang II–infused hypertensive rats suggests the involvement of
MAP kinase in this model of hypertension. Support for this view is our
demonstration that administration of the MEK inhibitor
PD-98059 reduces MABP and MAP kinase activity in the kidney of Ang
II–infused hypertensive rats. From these observations, we conclude
that the increase in Ras and MAP kinase activity caused by Ang II
contributes to the development of hypertension. It is unlikely that the
inhibitors of Ras and MEK had a nonspecific effect on the
cardiovascular system, because they did not alter
arterial blood pressure in normotensive rats. Whether the
decrease in MABP produced by Ras/MAP kinase inhibitors in
Ang II–infused rats is primarily due to a decrease in
peripheral vascular resistance or in cardiac output remains
to be determined.
It is well established that hypertrophy of VSMCs is an important feature of hypertension and that the structural changes in the vessel walls contribute to the increase in vascular resistance that promotes hypertension.34 Renin-Ang II–dependent hypertension is associated with pathological changes in the cardiovascular system, including vascular injury and remodeling.35 36 37 In the present study, in animals infused with Ang II, morphological and histological analyses of the kidney revealed extensive structural alterations, particularly hypertrophy of the vessel wall, which resulted in lumen compromise and an "onion-skin" pattern in small arteries. In our experiments, the infusion of FPT III in animals that received Ang II diminished the vascular pathological alterations, including the severity and number of vascular lesions and hypertrophy in the kidney. These results suggest that the increase in Ras activity also contributes to vascular damage associated with Ang II–induced hypertension. Neutralization of Ras with its antibody has been reported to inhibit Ang II–induced VSMC proliferation.38 These observations raise the possibility that activation of the Ras/MAP kinase pathway might initiate structural changes in the vasculature that contribute to the development of Ang II–induced hypertension.
The mechanism by which Ang II infusion increases Ras and MAP kinase activity in vivo is not known. Ang II has been shown to stimulate Ras/MAP kinase activity via metabolites of arachidonic acid generated through CYP450, mainly 20-HETE, and, to a lesser degree, by the lipoxygenase product 12-HETE.17 Ang II has also been shown to increase 20-HETE production in renal vessels, which contributes to the renal vasoconstrictor and pressor action of the peptide.29 20-HETE stimulates Ras and MAP kinase activity in VSMCs and promotes VSMC contraction and proliferation. Therefore, it is possible that the structural changes in the vasculature and the hypertension caused by Ang II infusion are mediated via activation of the Ras/MAP kinase pathway by 20-HETE. Support for this view is our demonstration that ABT, which has been shown to inhibit CYP450 activity and to reduce 20-HETE production in spontaneously hypertensive rats and in the deoxycorticosterone-acetate salt models of hypertension,14 15 diminished the elevation in CYP450 activity and the development of Ang II–induced hypertension. Moreover, the effect of ABT to minimize the development of Ang II–induced hypertension in rats was associated with a decrease in Ras and MAP kinase activity in the kidney. Furthermore, in animals treated with ABT, the Ang II–induced renal vascular lesions were minimized. Although our data with ABT support the involvement of 20-HETE in an Ang II–induced increase in blood pressure and vascular lesions, we cannot exclude the contribution of other prohypertensive eicosanoids or mechanisms unrelated to eicosanoids. Moreover, our studies do not permit us to draw any conclusion as to whether the renal protective action of inhibitors of Ras farnesyl transferase and CYP450 is due to their direct effect on these pathways or a result of decrease in blood pressure. Additional studies with other antihypertensive agents would be required to address this issue.
In conclusion, the present study demonstrates that the activation of MAP kinase via Ras/MEK by metabolites of arachidonic acid generated through CYP450, most likely 20-HETE, contributes to the vascular injury, hypertrophy, and hypertension caused by Ang II in rats. Whether activation of Ras/MAP kinase also contributes to other models of hypertension and vascular structural alterations remains to be determined. Our recent studies indicate that Ras/MAP kinase also contributes to the development of high blood pressure in deoxycorticosterone acetate salt model of hypertension.23
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Acknowledgments |
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This work was supported by National Institutes of Health grant 19134-25 (to Dr Malik), an American Heart Association Beginner’s Grant-in-Aid (to Dr Muthalif), and an American Heart Association Grant-in-Aid (to Dr Benter). We thank Omar Z. Malik and Sara Alikhani, who were supported by Young Memphis Scholar’s summer program from the National Science Foundation, for their participation in this work. The authors gratefully acknowledge Dr Lauren Cagen for scientific discussions and Jin Emerson Cobb for editorial assistance.
Received February 24, 2000; first decision March 22, 2000; accepted May 1, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ichikawi I, Harris RC. Angiotensin actions in the kidney: renewed insight into the old hormone. Kidney Intl. 1991;40:583–596.[Medline] [Order article via Infotrieve]
2. Timmermans PB, Wong PC, Chui AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Ang II receptors and Ang II receptor antagonists. Pharmacol Rev. 1993;45:205–251.[Medline] [Order article via Infotrieve]
3. Hughes AD. Molecular and cellular mechanisms of action of Ang II (AT1) receptors in vascular smooth muscle. J Hum Hypertens. 1998;45:275–281.
4.
Xi XP, Graf K, Goetz S, Fleck E, Hsueh WA, Law RE.
Central role of the MAP kinase pathway in Ang II–mediated DNA
synthesis and migration in rat VSMC. Arterioscler Thromb Vasc
Biol. 1999;19:73–82.
5. Weber H, Taylor DS, Molloy CJ. Ang II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells: correlation with the expression of specific endogenous growth factors and reversal by suramin. J Clin Invest. 1994;93:788–798.
6.
Berk BC, Corson MA. Ang II signal transduction in
vascular smooth muscle: role of tyrosine kinases. Circ Res. 1997;80:607–616.
7.
Griendling KK, Ushio-Fukai M, Lassegue B, Alexander
RW. Ang II signaling in vascular smooth muscle: new concepts.
Hypertension. 1991;29:366–373.
8.
Schieffer B, Paxton WG, Chai Q, Marrero MB, Bernstein
KE. Ang II controls p21 ras activity via
pp60 c-src. J Biol Chem. 1994;271:10329–10333.
9.
Muthalif MM, Benter IF, Uddin MR, Harper JL, Malik KU.
Signal transduction mechanisms involved in Ang (1-7)-stimulated
arachidonic acid release and prostanoid synthesis in
rabbit aortic smooth muscle cells. J Pharmacol Exp
Ther. 1998;284:388–398.
10. Rao GN, Lassegue B, Alexander RW, Griendling KK. Ang II stimulates phosphorylation of high-molecular-mass cytosolic PLA2 in VSMC. Biochem J. 1994;299:197–201.
11.
Shinoda J, Kozawa O, Suzuki A, Watanabe-Tomita Y, Oiso
Y, Uematsu T. Mechanism of Ang II-induced arachidonic
acid metabolite release in aortic smooth muscle cell: involvement of
PLD. Eur J Endocrinol. 1997;136:207–212.
12. Nasjletti A, Malik KU. Interrelations between prostaglandins and vasoconstrictor hormones: contribution to blood pressure regulation. Fed Proc. 1982;Al:2394–2399.
13. Nasjletti A. The role of eicosanoids in angiotensin-dependent hypertension. Hypertension. 1997;31:194–200.
14. McGiff JC, Steinberg M, Quilly J. Missing links: CYP450 arachidonate products, a new class of lipid mediators. Trends Cardiovasc Med. 1996;6:4–10.
15.
Harder DR, Gebremedhin D, Narayanan J, Jefcoat C, Falck
JR, Campbell WB, Roman RJ. Formation and action of a P450 4A metabolite
of arachidonic acid in cat cerebral microvessels.
Am J Physiol. 1994;266:H2098–H2107.
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.
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.
18.
Muthalif MM, Benter IF, Karzoun N, Fatima S, Harper J,
Uddin MR, Malik KU. 20-HETE mediates
calcium/calmodulin-dependent protein kinase II-induced MAP
kinase activation in VSMC. Proc Natl Acad Sci U S A. 1998;95:12701–12706.
19.
Uddin MR, Muthalif MM, Karzoun NA, Benter IF, Malik KU.
CYP450 metabolites mediate norepinephrine-induced
mitogenic signaling. Hypertension. 1998;31:242–247.
20.
Touyz RM, El Mabrouk M, He G, Wu XH, Schiffrin EL.
MAP/extracellular signal-regulated kinase inhibition attenuates Ang
II–mediated signaling and contraction in spontaneously hypertensive
rat VSMCs. Circ Res. 1999;84:505–515.
21.
Touyz RM, He G, Deng LY, Schriffin EL. Role of
extracellular signal-regulated kinases in Ang II–stimulated
contraction of smooth muscle cells from human resistance arteries.
Circulation. 1999;99:392–399.
22. Diz DI, Baer PG, Nasjletti A. Ang II-induced hypertension in the rat. Effect on the plasma concentration, renal excretion and tissue release of prostaglandins. J Clin Invest. 1983;72:466–477.
23.
Muthalif MM, Benter IF, Khandekar Z, Gaber L, Estes A,
Malik S, Parmentier J-H, Manne V, Malik KU. Contribution of Ras
GTPase/MAP kinase and CYP450 metabolites to
deoxycorticosterone-salt-induced hypertension. Hypertension. 2000;35:457–463.
24.
Hermann C, Martin G, Wittinghofer A. Quantitative
analysis of the complex between p21 ras
and the Ras-binding domain of the human Raf-1 protein kinase.
J Biol Chem. 1995;270:2901–2905.
25. De Rooij J, Bos JL. Minimal Ras-binding domain of Raf-1 can be used as an activation-specific probe for Ras. Oncogene. 1997;14:623–625.[Medline] [Order article via Infotrieve]
26. Vojtek AB, Hollenberg SM, Cooper JA. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993;74:205–214.[Medline] [Order article via Infotrieve]
27.
Fabian JR, Vojtek AB, Cooper JA, Morrison DK. A single
amino acid change in Raf-1 inhibits Ras binding and alters Raf-1
function. Proc Natl Acad Sci U S A. 1994;91:5982–5986.
28.
Kisch ES, Jaffe A, Knoll E, Stern N. Role of
lipoxygenase pathway in Ang II–induced
vasoconstriction in the human placenta. Hypertension. 1997;29:796–801.
29. Alonso-Garcia A, Greene AS, Kurth TM, Cowley AW, Roman RJ. 20-HETE contributes to the renal vasoconstrictor actions of Ang II. FASEB J. 1999;13:A389. Abstract.
30.
Rao GN, Baas AS, Glasgow WC, Eling TE, Runge MS,
Alexander RW. Activation of MAP kinases by arachidonic
acid and its metabolites in VSMC. J Biol Chem. 1994;269:32586–32591.
31.
Dulin NO, Alexander LD, Harwalkar S, Falck JR, Douglas
JG. PLA2-mediated activation of MAP kinase by Ang
II. Proc Natl Acad Sci U S A. 1998;95:8098–8102.
32.
Takahashi T, Kawahara Y, Okuda M, Ueno H, Takeshita A,
Yokoyama M. Ang II stimulates MAP kinases and protein synthesis by a
Ras-independent pathway in VSMC. J Biol Chem. 1997;272:16018–16022.
33.
Eguchi S, Matsumoto T, Motley ED, Utsunomiya H, Inagami
T. Identification of an essential signaling cascade for MAP
kinase-activation by Ang II in cultivated rat VSMC: possible
requirement of Gq-mediated
p21 ras activation coupled to a
Ca2+/calmodulin tyrosine kinase.
J Biol Chem. 1996;271:14169–14175.
34.
Owens GK, Schwartz SM. Alterations in vascular smooth
muscle mass in spontaneously hypertensive rat: role of cellular
hypertrophy, hyperploidy, and hyperplasia. Circ
Res. 1982;51:280–289.
35. Unger T, Culman J, Gohlke P. Ang II receptor blockade and end-organ protection: pharmacological rationale and evidence. J Hypertens.1998;16(suppl):S3–S9.
36. Nishikawa K. Ang II AT1 receptor antagonism and protection against cardiovascular end-organ damage. J Hum Hypertens. 1998;12:301–309.[Medline] [Order article via Infotrieve]
37. Zanchetti A. Impact of hypertension and antihypertensive treatment on organ damage. Am J Cardiol. 1999;84:18K–24K.[Medline] [Order article via Infotrieve]
38. Scieffer B, Drexler H, Ling BN, Marrero MB. G protein-coupled receptors control vascular smooth muscle cell proliferation via ppboc-src and P21ras. Am J Physiol. 1997;C2019–C2030.
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 F. Park, W. E. Sweeney, G. Jia, R. J. Roman, and E. D. Avner 20-HETE Mediates Proliferation of Renal Epithelial Cells in Polycystic Kidney Disease J. Am. Soc. Nephrol., October 1, 2008; 19(10): 1929 - 1939. [Abstract] [Full Text] [PDF]
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 S.-G. Wei, Y. Yu, Z.-H. Zhang, R. M. Weiss, and R. B. Felder Angiotensin II-Triggered p44/42 Mitogen-Activated Protein Kinase Mediates Sympathetic Excitation in Heart Failure Rats Hypertension, August 1, 2008; 52(2): 342 - 350. [Abstract] [Full Text] [PDF]
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 C.-J. Liang, H. E. Ives, C.-M. Yang, and Y.-H. Ma 20-HETE inhibits the proliferation of vascular smooth muscle cells via transforming growth factor- J. Lipid Res., January 1, 2008; 49(1): 66 - 73. [Abstract] [Full Text] [PDF]
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 C. S. Escano Jr., L. B. Keever, A. A. Gutweiler, and B. T. Andresen Angiotensin II Activates Extracellular Signal-Regulated Kinase Independently of Receptor Tyrosine Kinases in Renal Smooth Muscle Cells: Implications for Blood Pressure Regulation J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 34 - 42. [Abstract] [Full Text] [PDF]
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T. Ishizuka, J. Cheng, H. Singh, M. D. Vitto, V. L. Manthati, J. R. Falck, and M. Laniado-Schwartzman 20-Hydroxyeicosatetraenoic Acid Stimulates Nuclear Factor-{kappa}B Activation and the Production of Inflammatory Cytokines in Human Endothelial Cells J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 103 - 110. [Abstract] [Full Text] [PDF]
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H. Singh, J. Cheng, H. Deng, R. Kemp, T. Ishizuka, A. Nasjletti, and M. L. Schwartzman Vascular Cytochrome P450 4A Expression and 20-Hydroxyeicosatetraenoic Acid Synthesis Contribute to Endothelial Dysfunction in Androgen-Induced Hypertension Hypertension, July 1, 2007; 50(1): 123 - 129. [Abstract] [Full Text] [PDF]
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 J.-S. Wang, H. Singh, F. Zhang, T. Ishizuka, H. Deng, R. Kemp, M. S. Wolin, T. H. Hintze, N. G. Abraham, A. Nasjletti, et al. Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 Adenovirus Circ. Res., April 14, 2006; 98(7): 962 - 969. [Abstract] [Full Text] [PDF]
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A. Sarkis, O. Ito, T. Mori, M. Kohzuki, S. Ito, J. Verbalis, A. W. Cowley Jr., and R. J. Roman Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1333 - F1340. [Abstract] [Full Text] [PDF]
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 K. Takeuchi, M. Renic, Q. C. Bohman, D. R. Harder, N. Miyata, and R. J. Roman Reversal of delayed vasospasm by an inhibitor of the synthesis of 20-HETE Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2203 - H2211. [Abstract] [Full Text] [PDF]
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F. A. Yaghini, C. Zhang, J.-H. Parmentier, A. M. Estes, N. Jafari, S. A. Schaefer, and K. U. Malik Contribution of Arachidonic Acid Metabolites Derived Via Cytochrome P4504A to Angiotensin II-Induced Neointimal Growth Hypertension, June 1, 2005; 45(6): 1182 - 1187. [Abstract] [Full Text] [PDF]
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B. T. Andresen, K. Shome, E. K. Jackson, and G. G. Romero AT2 receptors cross talk with AT1 receptors through a nitric oxide- and RhoA-dependent mechanism resulting in decreased phospholipase D activity Am J Physiol Renal Physiol, April 1, 2005; 288(4): F763 - F770. [Abstract] [Full Text] [PDF]
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 E. R. Isenovic, D. B. Jacobs, M. H. Kedees, Q. Sha, N. Milivojevic, K. Kawakami, G. Gick, and J. R. Sowers Angiotensin II Regulation of the Na+ Pump Involves the Phosphatidylinositol-3 Kinase and p42/44 Mitogen-Activated Protein Kinase Signaling Pathways in Vascular Smooth Muscle Cells Endocrinology, March 1, 2004; 145(3): 1151 - 1160. [Abstract] [Full Text] [PDF]
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 T. L. Kaduce, X. Fang, S. D. Harmon, C. L. Oltman, K. C. Dellsperger, L. M. Teesch, V. R. Gopal, J. R. Falck, W. B. Campbell, N. L. Weintraub, et al. 20-Hydroxyeicosatetraenoic Acid (20-HETE) Metabolism in Coronary Endothelial Cells J. Biol. Chem., January 23, 2004; 279(4): 2648 - 2656. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, S. Kimura, A. Nishiyama, T. Shokoji, M. Rahman, and Y. Abe ROS During the Acute Phase of Ang II Hypertension Participates in Cardiovascular MAPK Activation But Not Vasoconstriction Hypertension, January 1, 2004; 43(1): 117 - 124. [Abstract] [Full Text] [PDF]
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K. M. Hoagland, A. K. Flasch, and R. J. Roman Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats Hypertension, October 1, 2003; 42(4): 669 - 673. [Abstract] [Full Text] [PDF]
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S. L. Amaral, K. G. Maier, D. N. Schippers, R. J. Roman, and A. S. Greene CYP4A metabolites of arachidonic acid and VEGF are mediators of skeletal muscle angiogenesis Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1528 - H1535. [Abstract] [Full Text] [PDF]
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B. T. Andresen, J. J. Linnoila, E. K. Jackson, and G. G. Romero Role of EGFR Transactivation in Angiotensin II Signaling to Extracellular Regulated Kinase in Preglomerular Smooth Muscle Cells Hypertension, March 1, 2003; 41(3): 781 - 786. [Abstract] [Full Text] [PDF]
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M. P. Massett, Z. Ungvari, A. Csiszar, G. Kaley, and A. Koller Different roles of PKC and MAP kinases in arteriolar constrictions to pressure and agonists Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2282 - H2287. [Abstract] [Full Text] [PDF]
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 S. Kagiyama, S. Eguchi, G. D. Frank, T. Inagami, Y. C. Zhang, and M. I. Phillips Angiotensin II-Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense Circulation, August 20, 2002; 106(8): 909 - 912. [Abstract] [Full Text] [PDF]
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 M. Alonso-Galicia, K. G. Maier, A. S. Greene, A. W. Cowley Jr., and R. J. Roman Role of 20-hydroxyeicosatetraenoic acid in the renal and vasoconstrictor actions of angiotensin II Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R60 - R68. [Abstract] [Full Text] [PDF]
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 T. Yamakawa, S.-i. Tanaka, Y. Yamakawa, J. Kamei, K. Numaguchi, E. D. Motley, T. Inagami, and S. Eguchi Lysophosphatidylcholine Activates Extracellular Signal-Regulated Kinases 1/2 Through Reactive Oxygen Species in Rat Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 752 - 758. [Abstract] [Full Text] [PDF]
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M. M. Muthalif, N. A. Karzoun, I. F. Benter, L. Gaber, F. Ljuca, M. R. Uddin, Z. Khandekar, A. Estes, and K. U. Malik Functional Significance of Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Angiotensin II-Induced Vascular Hyperplasia and Hypertension Hypertension, February 1, 2002; 39(2): 704 - 709. [Abstract] [Full Text] [PDF]
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 R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]
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 K. M. Hoagland, K. G. Maier, C. Moreno, M. Yu, and R. J. Roman Cytochrome P450 metabolites of arachidonic acid: novel regulators of renal function Nephrol. Dial. Transplant., December 1, 2001; 16(12): 2283 - 2285. [Full Text] [PDF]
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M. Seyedabadi, A. K. Goodchild, and P. M. Pilowsky Differential Role of Kinases in Brain Stem of Hypertensive and Normotensive Rats Hypertension, November 1, 2001; 38(5): 1087 - 1092. [Abstract] [Full Text] [PDF]
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J.-H. Parmentier, M. M. Muthalif, A. T. Nishimoto, and K. U. Malik 20-Hydroxyeicosatetraenoic Acid Mediates Angiotensin II-Induced Phospholipase D Activation in Vascular Smooth Muscle Cells Hypertension, February 1, 2001; 37(2): 623 - 629. [Abstract] [Full Text] [PDF]
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J.-H. Parmentier, M. M. Muthalif, A. E. Saeed, and K. U. Malik Phospholipase D Activation by Norepinephrine Is Mediated by 12(S)-, 15(S)-, and 20-Hydroxyeicosatetraenoic Acids Generated by Stimulation of Cytosolic Phospholipase A2. TYROSINE PHOSPHORYLATION OF PHOSPHOLIPASE D2 IN RESPONSE TO NOREPINEPHRINE J. Biol. Chem., May 4, 2001; 276(19): 15704 - 15711. [Abstract] [Full Text] [PDF]
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