(Hypertension. 2000;35:457.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Contribution of Ras GTPase/MAP Kinase and Cytochrome P450 Metabolites to Deoxycorticosterone-Salt–Induced Hypertension
From the Departments of Pharmacology (M.M.M., Z.K., A.E., S.M., J.-H.P., K.U.M.) and Pathology (L.G.), University of Tennessee, and the Southern College of Optometry, Division of Biomedical Sciences (I.F.B.), Memphis, Tenn; and the Department of Oncology Drug Discovery (V.M.), Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.
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 recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt–induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166±5 mm Hg, n=19) compared with that of normotensive controls (95±5 mm Hg, n=7) (P<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139±4 mm Hg (n=14) and 126±1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt–induced hypertension and associated vascular pathology consequent to activation of CYP450.
Key Words: Ras • MAP kinase • DOCA • pathology • cytochrome P450
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Several vasoactive agents, including norepinephrine, angiotensin II (Ang II), and endothelin-1, promote arachidonic acid release from tissue lipids via activation of
1 lipases.1 2 3 Arachidonic acid is metabolized by cyclooxygenase into prostaglandins and thromboxane A2, by lipoxygenase into leukotrienes and HETE (5-, 12-, and 15-HETE), and by cytochrome P450 (CYP450) into epoxyeicosatrienoic acid and 12-, 19-, and 20-HETE.4 5 6 7 Some of the products of arachidonic acid formed via lipoxygenase and CYP450 increase vascular tone and have been implicated in the vascular actions of Ang II.8 9 10 11 These metabolites of arachidonic acid have also been reported to cause activation of Ras and mitogen-activated protein (MAP) kinase.12 Moreover, MAP kinase mediates Ang II– or norepinephrine-induced proliferation of vascular smooth muscle cells.13 14 15 The hypertension produced by Ang II or by aortic coarctation has also been shown to be dependent on the lipoxygenase metabolites of arachidonic acid.10 16 Recently, it was shown that 20-HETE contributes to the increase in blood pressure in spontaneously hypertensive, deoxycorticosterone acetate (DOCA)-salt–induced, and Ang II–induced models of hypertension.17 18 19 These observations and the demonstration that a CYP450 inhibitor reduces Ras activation and the development of Ang II–induced hypertension19 suggest that the CYP450 metabolite 20-HETE raises blood pressure by activating the Ras/MAP kinase pathway. Whether the Ras/MAP kinase pathway is also involved in Ang II–independent models of hypertension is not known. One such model is hypertension induced by DOCA (an analogue of aldosterone) in rats drinking a 1% saline solution.20 Administration of DOCA causes retention of salt and water, increased plasma volume, and decreased renin secretion and consequently decreases Ang II levels.21 However, several other factors, such as catecholamine, vasopressin, and endothelin-1, also contribute to the development of DOCA-salt hypertension.22 23 24 25 26 27 28 Because these factors are known to increase arachidonic acid release and MAP kinase activity,1 3 29 30 it is possible that CYP450 metabolites of arachidonic acid, by activating Ras/MAP kinase, contribute to the development of DOCA-salt hypertension in rats. To test this hypothesis, we investigated the effect of various inhibitors of Ras, MAP kinase kinase (MEK), and CYP450 on the development of DOCA-salt hypertension and/or on the associated vascular injury and hypertrophy. |
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Materials
DOCA, NaCl, sodium pentobarbital, lauric acid, and heparin were from Sigma Chemical Co; the farnesyl protein transferase inhibitors FPT III and BMS-191563 were from Calbiochem and a gift from Bristol-Myers Squibb, respectively; 2ML1 osmotic minipump from Alzet Corp; H-Ras monoclonal antibody from Santa Cruz Biotechnology; the CYP450 inhibitor ABT from Acros; and PD-98059, MAP kinase, and phosphospecific MAP kinase antibodies from New England Biolabs.
Experimental Procedures
DOCA-Salt Hypertension
Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass) weighing 200 g were kept at 24°C under controlled conditions of light (6 AM to 6 PM) and humidity (50%). The animals were fed standard rat chow (Ralston Purina Co) containing sodium (174 mEq/kg) and potassium (282 mEq/kg) and had free access to the food and water. All procedures were done in accordance with institutional guidelines for animal research. The rats were anesthetized with a ketamine-xylazine mixture. A small midline abdominal incision (2 cm) was made to ligate the left renal artery and vein and dissect out the left kidney. The abdominal incision was sutured and the skin stapled, and the animal was allowed to recover from anesthesia for 3 days. The animals were given standard chow and tap water containing 1% NaCl. Five animals were sham-operated without removal of the kidney and were given tap water containing 1% NaCl. The uninephrectomized animals were injected intramuscularly with a suspension of DOCA in sesame oil (30 mg/kg per week, 0.2 mL) or vehicle for 6 weeks as described.31 To study the effects of inhibitors of Ras farnesyl transferase, MEK, and CYP450 on DOCA-salt–induced hypertension, rats were divided into various groups. Inhibitors of Ras farnesyl transferase (FPT III and BMS-191563) and MEK (PD-98059) were administered with osmotic minipumps (model 2ML1) during the last week of DOCA-salt treatment. The osmotic minipumps were filled with FPT III (1.2 mg), BMS-191563 (5 mg), PD-98059 (5 mg), or vehicle and placed in the abdominal cavity. The osmotic minipump delivered FPT III (138 ng/min), BMS-191563 (694 ng/min), or PD-98059 (694 ng/min) over a period of 5 days. In another group of rats, the effect of the CYP450 inhibitor ABT (50 mg/kg) was evaluated. ABT was administered intraperitoneally every second day for 6 days. A group of sham-operated rats with intact kidneys was used as a control.
Blood Pressure Measurement
Animals were anesthetized with sodium pentobarbital (60 mg/kg), and the left femoral artery was exposed surgically. A small incision was made in the femoral artery, and a catheter was inserted and connected to a pressure transducer (Grass model 7m, Grass Instruments) for blood pressure measurement. Blood pressure was recorded on a polygraph (model 7D; Grass polygraph). The MABP was expressed as mm Hg. After blood pressure measurement, the thoracic cavity was exposed and the kidney and hearts were removed. The heart tissues were rapidly frozen in liquid nitrogen for the measurement of Ras and MAP kinase protein and activity levels, and the kidney was used for histological examination and measurement of CYP450 activity.
CYP450 4A Activity
CYP450 4A activity, measured as lauric acid 12-hydroxylase activity, was determined according to the method described earlier,32 with small modifications. Kidney protein extracts (200 µL, 0.5 mg) were mixed with 100 µL of buffer containing 0.4% NAD (wt/vol), 0.4% NADP (wt/vol), 0.75% glucose 6-phosphate (wt/vol), 1% BSA (wt/vol), 1% glucose 6-phosphate dehydrogenase (vol/vol), 0.05 mmol/L MgCl2, 0.05 mmol/L Tris-HCl, pH 7.6, and the volume was adjusted to 1 mL with Tris-HCl (pH 7.6). The enzymatic reaction was initiated by the addition of 25 µL of [14C]lauric acid solution (5 mmol/L, 5000 dpm/nmol) and continued for 30 minutes at 37°C. [14C]lauric acid solution was prepared by diluting [14C]lauric acid (55 mCi/mmol, Amersham) and unlabeled lauric acid in ethanol. The reaction was stopped by adding 100 µL of 0.2N acetic acid. The metabolites were extracted twice in 3 mL of ethyl acetate, and the organic phase was dried under nitrogen. Samples were then resuspended and sonicated in 50 µL methanol and separated by thin-layer chromatography with hexane, ethyl ether, and acetic acid as the solvent system (2:8:0.1 vol/vol). Formation of 12-hydroxylauric acid was detected with Instant Imager (Packard Instruments).
Measurement of Ras, MAP Kinase, and Phosphospecific MAP Kinase Levels by Western Blotting
Frozen heart tissues were processed for Western blot analysis as described.33 Briefly, the tissues (200 mg) were powdered in liquid nitrogen with a mortar and pestle and homogenized in 1 mL of buffer (mmol/L: HEPES 20 [pH 7.5], ß-glycerophosphate 20, sodium pyrophosphate 20, sodium vanadate 0.2, EDTA 2, sodium fluoride 20, benzamidine 10, and DTT 1, and 20 µg/mL leupeptin) with a Dounce homogenizer. Cell debris was removed by centrifugation (14 000g for 10 minutes at 4°C), and the supernatant was stored in aliquots at -70°C. Proteins (200 µg) were resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE 12%) and transferred to nitrocellulose membrane. The blots were blocked with 3% BSA in TBS buffer (20 mmol/L Tris, 137 mmol/L NaCl, pH 7.6) at room temperature for 1 hour and then incubated for 2 hours with MAP kinase or Ras or phosphospecific MAP kinase antibodies (1:1000 dilution). The blots were developed with biotinylated secondary antibody and horseradish peroxidase, and signals were detected with ECL Western blotting detection reagents (Amersham).
Measurement of Ras Activity
The Ras binding domain of Raf-1, immobilized by fusion to glutathione S-transferase (GST) and bound to glutathione beads, was used as an affinity reagent to precipitate Ras-GTP from cell lysates. Affinity-precipitated Ras was detected by Western blotting with anti-Ras antibodies.
GST-RBD Preparation
The plasmid pGEX encoding amino acids 1 to 149 of the Ras-binding domain (RBD) of Raf was used (kindly provided by Dr Senthilkumar Muthuswamy, Harvard University). The plasmid was transformed into Escherichia coli strain DH5
for protein expression.34 35 An overnight culture of bacteria (2 L) was grown at 37°C in LB medium containing 100 µg/mL ampicillin. Expression of GST-RBD protein was induced overnight at 30°C with 0.1 mmol/L isopropyl-1-thio-ß-D-galactopyranoside at a cell density of 
0.5 A600. The bacterial culture was centrifuged at 5000g for 20 minutes and washed once with ice-cold buffer (25 mmol/L HEPES [pH 7.5], 150 mmol/L NaCl). The pellet was sonicated for 4 minutes (4 bursts of 1-minute duration) in 10 mL of lysis buffer (20 mmol/L HEPES [pH 7.5], 120 mmol/L NaCl, 10% glycerol, 2 mmol/L EDTA, 10 µg/mL leupeptin, 10 µg/mL aprotinin). The lysates were gently stirred for 30 minutes at 4°C and centrifuged at 10 000g for 30 minutes to remove the pellet. NP-40 was added to a final concentration of 0.5% to the supernatant containing crude GST-RBD, and the supernatant was then incubated with 500 µL of prewashed glutathione sepharose 4B beads (Pharmacia Biotech, Sweden) for 30 minutes at 4°C. The beads were isolated by centrifugation and washed 3 times with ice-cold PBS.
Affinity Precipitation of Ras-GTP
One milligram of proteins isolated from heart tissues was incubated with GST-RBD bound to 75 µL of glutathione sepharose beads on a rocker for 1 hour at 4°C. The beads were then washed 3 times with lysis buffer (100 mmol/L HEPES [pH 7.5], 1 mol/L NaCl, 1% NP-40, 10% glycerol, 0.25% sodium vanadate, 2 mmol/L PMSF, 10 µg leupeptin, and 10 µg/mL aprotinin) and resuspended in sample buffer (10% glycerol, 60 mmol/L Tris HCl [pH 6.8], 2% SDS, 30 mmol/L ß-mercaptoethanol, 0.006% bromphenol blue). Proteins were resolved by SDS-PAGE, transferred to a nitrocellulose membrane, probed with H-Ras-235 monoclonal antibody, and detected as described above.
Histological Examination
The kidneys removed from the DOCA-salt hypertensive rats with or without treatment with FPT III were fixed in formalin and then divided into 3 parts by 2 mid-transverse sections. To ensure homogeneous sampling, the middle part, 0.5 cm thick, was selected for histological examination in all animals. The fixed sections were processed for paraffin embedding, and hematoxylin-eosin–stained sections were prepared by standard techniques. Two to 4 cross sections representative of the renal cortex, renal medulla, and pelvis were examined on each case. 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 the presence and absence of the following features: (1) fibrinoid necrosis; (2) alterations in the endothelial or smooth muscle cells, such as cellular hypertrophy, pylenosis, single-cell necrosis, or cellular dropout; (3) hemorrhage in the media (hematomedia); and (4) concentric mural hypertrophy with or without "onionskin" change.
Statistical Analysis
Values are reported as mean±SEM. The data were analyzed by 1-way ANOVA, and the difference between the means for multiple comparisons was determined with the Newman-Keuls test; a value of P<0.05 was considered statistically significant.
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Effects of FPT III, BMS-191563, PD-98059, and ABT on MABP in DOCA-Salt Hypertensive Rats
Administration of DOCA (30 mg/kg per week IM) and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly increased MABP (166±5 mm Hg) compared with that of normotensive rats (95±5 mm Hg) (P<0.005) and rats treated with salt (108±2 mm Hg), salt plus nephrectomy (112± 11 mm Hg), or DOCA plus nephrectomy (121±13 mm Hg) (Figure 1). Infusion of the Ras-farnesyl transferase inhibitors FPT III or BMS-191563 during the last 5 days of DOCA-salt treatment significantly reduced MABP to 139±4 and 126±1 mm Hg, respectively (P<0.05) (Figure 2). The inhibitor of MEK PD-98059 also reduced MABP in hypertensive rats to 120 mm Hg (Figure 2). Treatment of DOCA-salt animals with the CYP450 inhibitor ABT also reduced MABP to 97±7 mm Hg (P<0.05).
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Values significantly different from Veh (P<0.05).
Effects of FPT III and ABT on Ras Activity in DOCA-Salt Hypertensive Rats
Protein extracts from the hearts of DOCA-salt hypertensive rats, normotensive controls, and hypertensive animals treated with inhibitors of Ras, MEK, and CYP450 were obtained. Ras protein levels were not altered with DOCA-salt treatment. Moreover, FPT III or ABT did not alter Ras protein levels in the hearts of DOCA-salt hypertensive rats (Figure 3A). CYP450 4A activity, measured as lauric acid hydroxylase activity, was elevated in the kidney of DOCA-salt hypertensive rats, and treatment with ABT attenuated this response (Figure 3B). It has been shown that Ras protein interacts with Raf and that the residues 51 to 131 of mammalian Raf-1 (called RBD) are sufficient to bind Ras-GTP but not Ras-GDP.36 37 RBD was expressed as a GST fusion protein and was purified with glutathione-sepharose beads (Figure 3C). The Ras activity, measured as Ras-GTP bound to the RBD of Raf, was increased in the DOCA-salt hypertensive rats. However, the Ras activity was decreased in the hearts of DOCA-salt hypertensive animals treated with FPT III or ABT (Figure 3D). Treatment of normotensive rats with these inhibitors did not show any significant changes in Ras protein and activity levels (data not shown).
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Effects of FPT III, PD-98059, and ABT on MAP Kinase Activity in DOCA-Salt Hypertensive Rats
Ras stimulates Raf by promoting its association with the plasma membrane and activates the MEK/MAP kinase pathway.38 Hence, we studied the effects of Ras, MAP kinase, and CYP450 inhibitors on the MAP kinase activity. Western blot analysis using the MAP kinase antibody showed that similar levels of ERK1 and ERK2 were present in heart extracts from normotensive and DOCA-salt hypertensive animals. Moreover, treatment of hypertensive animals with inhibitors of Ras, MEK, and CYP450 did not decrease the levels of protein (Figure 4A). However, activation of MAP kinase, as measured by phosphospecific MAP kinase antibody, showed marked elevation of phosphorylated MAP kinase levels with DOCA-salt treatment. This MAP kinase activity was attenuated in the hearts of hypertensive animals treated with FPT III, PD-98059, or ABT (Figure 4B).
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Effect of FPT III on the Morphological Changes in the Kidney of DOCA-Salt Hypertensive Rats
The kidneys from the uninephrectomized animals with DOCA-salt–induced hypertension, as expected, were enlarged. Microscopic examination of these kidneys demonstrated a generalized concentric hypertrophy of small arteries and multiple foci of fibrinoid necrosis in the small and large arteries. Foci of interstitial fibrosis, tubular atrophy, and chronic inflammation were also identified (Figure 5A). DOCA-salt hypertensive animals treated with FPT III in the last week of DOCA-salt treatment (5 weeks) did not exhibit any evidence of hyperplastic arteriosclerosis, arterial necrosis, or interstitial scarring (Figure 5B). These kidneys were essentially unremarkable, except for the presence of red blood cell casts in the renal tubules. The effects of BMS-191563 and PD-98059 on the morphological changes produced in the kidney of DOCA-salt hypertensive rats were not examined. The effect of CYP450 inhibition to minimize renal vascular hypertrophy in DOCA-salt hypertensive rats has recently been reported.18
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Discussion |
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It was reported previously that the CYP450 metabolites of arachidonic acid, especially 20-HETE, activate the Ras/MAP kinase pathway,12 which in turn promotes vascular hyperplasia.14 The present study demonstrates that Ras/MAP kinase, probably activated by the CYP450 metabolite 20-HETE, contributes to the development of DOCA-salt hypertension and the associated renal hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis in rats.
In our study, administration of DOCA-salt to uninephrectomized rats produced a significant rise in MABP compared with that in animals with uninephrectomy, DOCA, or salt treatment alone. The increase in blood pressure in DOCA-salt hypertensive rats was associated with an increase in Ras activity in the heart, indicating involvement of Ras in the development of DOCA-salt hypertension. Ras is activated upon binding to the membrane, and this process is initiated by farnesylation of Ras by farnesyl transferase.39 Our finding that FPT III and BMS-191563, inhibitors of Ras farnesylation, reduced arterial blood pressure supports our contention that the development of DOCA-salt hypertension is dependent on the activity of Ras. The decrease in blood pressure in DOCA-salt hypertensive rats produced by FPT III was smaller than that caused by BMS-191563. This is probably due to the infusion of smaller amounts of FPT III.
The mechanism by which Ras promotes the development of DOCA-salt hypertension most likely involves activation of MEK and MAP kinase pathways,12 for the following reason. In DOCA-salt hypertensive rats, cardiac MAP kinase activity was increased, whereas it was reduced in animals treated with Ras inhibitors. Moreover, the MEK inhibitor PD-98059 also diminished the development of DOCA-salt–induced hypertension in rats. The effect of inhibitors of Ras and MEK to minimize the development of hypertension in DOCA-salt–treated rats is unlikely to be due to a nonspecific effect on the cardiovascular system, because they did not alter arterial blood pressure in normotensive rats. Whether the decrease in arterial blood pressure produced by the inhibitors of Ras and MEK in DOCA-salt hypertensive rats is due to a decrease in peripheral vascular resistance and/or cardiac output remains to be established.
We have reported that the Ras/MAP kinase pathway contributes to the elevation of MABP in Ang II–dependent hypertension in rats.19 However, in the DOCA-salt model, Ang II levels are markedly diminished, and other vasoactive agents, such as catecholamines, vasopressin, and endothelin-1, contribute to the development of hypertension.22 23 24 25 26 27 28 Because these agents have also been reported to increase MAP kinase activity in vascular smooth muscle cells, it is possible that activation of the Ras/MAP kinase pathway promotes the development of hypertension in this model. It has been reported that endothelin-1 promotes DOCA-salt hypertension by stimulating the production of 20-HETE because the endothelin A receptor blocker BMS-182874 reduces arterial blood pressure and the urinary excretion of 20-HETE.18 Moreover, CYP450 inhibitors also reduced arterial blood pressure in DOCA-salt hypertensive rats.18 It is possible that the Ras/MAP kinase pathway is activated by 20-HETE production by endothelin-1 and other vasoactive agents in DOCA-salt hypertension. Supporting this view is our finding that ABT, which inhibited CYP450 activity (Figure 3B) and decreased the production of 20-HETE in the kidney,17 reduced arterial blood pressure and decreased Ras and MAP kinase activities in the hearts of DOCA-salt hypertensive rats. The effects of the various inhibitors used in this study to block Ras, MAP kinase, and CYP450 activation did not correlate with their effect to reduce MABP. Therefore, it is possible that other signaling mechanisms might also contribute to DOCA-salt–induced hypertension.
It is well established that hypertension produced by prolonged treatment with DOCA-salt in uninephrectomized rats is associated with nephrosclerosis, enlargement of the heart and kidney, and vasculitis.40 Hypertrophy is an important feature of hypertension, and structural changes in vessel wall contribute to an increase in vascular resistance.41 42 43 In the present study, DOCA-salt treatment in rats also caused concentric hypertrophy of small arteries, multiple foci of fibrinoid necrosis in small and large arteries, and tubular atrophy within the kidney. In DOCA-salt hypertensive rats treated with the Ras inhibitor FPT III, there was no evidence of morphological alterations, such as hyperplastic arteriosclerosis, arterial necrosis, or interstitial scarring. The effect of FPT III to ameliorate structural alterations in the vasculature of DOCA-salt hypertensive rats could also be due to a decrease in MAP kinase activity. An increase in MAP kinase activity has been shown to mediate the effect of 20-HETE on vascular smooth muscle cell proliferation.14 Inhibition of CYP450 activity with CoCl2 has been reported to decrease organ hypertrophy and renal injury and to attenuate the effect of endothelin-1 to stimulate vascular hyperplasia in DOCA-salt hypertensive rats.18 Therefore, it is possible that the CYP450 metabolite 20-HETE, generated in response to vasoactive agents, increases vascular tone and leads to the development of DOCA-salt hypertension in rats by causing vascular hypertrophy and hyperplasia.
In conclusion, the present study demonstrates that the Ras/MAP kinase pathway, probably activated by a metabolite of arachidonic acid formed via CYP450, most likely 20-HETE, promotes development of DOCA-salt hypertension and hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis in rats.
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Acknowledgments |
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This work was supported by National Institute of Health grant 19134-25 (to K.U.M.) and American Heart Association Beginners Grant-in-Aid (to M.M.M.)
Received September 14, 1999; first decision October 19, 1999; accepted November 10, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Muthalif MM, Benter IF, Uddin MR, Harper JL, Malik KU. Ca2+/calmodulin-dependent protein kinase A mediates activation of MAP kinase and cytosolic phospholipase A2 in norepinephrine-induced arachidonic acid release in rabbit aortic smooth muscle cells. J Biol Chem. 1996;271:30149–30157.
2.
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.
3.
Wright HM, Malik KU. Prostacyclin formation elicited by endothelin-1 in rat aorta is mediated via phospholipase D activation and not phospholipase C or A2. Circ Res. 1996;79:271–276.
4. Moncada S, Vane JR. Pharmacology and endogenous role of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev. 1978;30:243–331.
5. McGiff JC. Prostaglandins, prostacyclin and thromboxanes. Annu Rev Pharmacol Toxicol. 1991;31:339–369.[Medline] [Order article via Infotrieve]
6.
Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983;220:568–575.
7.
Capdevilla J, Marnett LJ, Chacos N, Prough RA, Estabrook RW. CYP-450 dependent oxygenation of arachidonic acid to HETE. Proc Natl Acad Sci U S A. 1982;79:767–770.
8. Natarajan R, Gonzales N, Lanting L, Nadler J. Role of the lipoxygenase pathway in Ang II–induced vascular smooth muscle cell hypertrophy. Hypertension. 1994;23:I-142–I-147.
9. McGiff JC, Steinberg M, Guilly J. Missing links: CYP-450 arachidonate products, a new class of lipid mediators. Trends Cardiovasc Med. 1996;6:4–10.
10. Nasjletti A. The role of eicosanoids in Ang II–dependent hypertension. Hypertension. 1997;31:194–200.
11. 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.
12.
Muthalif MM, Karzoun N, Fatima S, Harper J, Uddin MR, Malik KU. 20-HETE mediates Ca2+/calmodulin-dependent protein kinase II-induced MAP kinase activation in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1998;95:12701–12706.
13.
Wen Y, Nadler JL, Gonzales N, Scott S, Clauser E, Natarajan R. Mechanisms of Ang II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase. Am J Physiol. 1996;271:C1212–C1220.
14.
Uddin MR, Muthalif MM, Karzoun NA, Benter IF, Malik KU. CYP-450 metabolites mediate norepinephrine-induced mitogen signaling. Hypertension. 1998;31:242–247.
15.
Seewald S, Seul C, Kettenhofen R, Bokemeyer D, Ko Y, Vetter H, Sachinidis A. Role of MAP kinase in the Ang II–induced DNA synthesis in vascular smooth muscle cells. Hypertension. 1998;31:1151–1156.
16.
Lin L, Balazy M, Pagano PJ, Nasjletti A. Expression of prostaglandin H2–mediated mechanism of vascular contraction in hypertensive rats: relation to lipoxygenase and prostacyclin synthase activities. Circ Res. 1994;74:197–205.
17.
Su P, Kaushal KM, Kroetz DL. Inhibition of renal arachidonic acid as hydroxylase activity with ABT reduces blood pressure in spontaneously hypertensive rats. Am J Physiol. 1998;275:R426–R438.
18.
Oyekan AO, McAward K, Conetta J, Rosenfeld L, McGiff JC. Endothelin-1 and CYP-450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension. Am J Physiol. 1999;276:R766–R775.
19. Benter I, Muthalif MM, Karzoun N, Fatima SF, Malik KU. Contribution of Ras GTPase to the development of Ang II-induced hypertension. FASEB J. 1999;13:A484. Abstract.
20. Selge H, Hall CE, Rowley EM. Malignant hypertension produced by treatment with DOCA and NaCl. Can Med Assoc J. 1943;49:88–92.
21.
Davis JO, Freeman RH. Mechanisms regulating renin release. Physiol Rev. 1976;56:1–50.
22. De Champlain J, Bouvier M, Droplet G. Abnormal regulation of the sympathoadrenal system in DOCA-salt hypertensive rats. Can J Physiol Pharmacol. 1987;65:1605–1614.[Medline] [Order article via Infotrieve]
23. Drolet G, Bouvier M, de Champlain Jr. Enhanced sympathoadrenal reactivity to hemorrhagic stress in DOCA-salt hypertensive rats. J Hypertens. 1989;7:237–242.[Medline] [Order article via Infotrieve]
24. Okada H, Suzuki H, Kanno Y, Saruta T. Effect of nonpeptide vasopressin receptor antagonists on developing, and established DOCA-salt hypertension in rats. Clin Exp Hypertens. 1985;17:469–483.
25.
Crofton JT, Share LS, Shade RE, Lee-Kwon WJ, Mannniong M, Sawyer WH. The importance of vasopressin in the development and maintenance of DOCA-salt hypertension in the rat. Hypertension. 1979;1:31–38.
26. Fujita K, Matsumura Y, Kita S, Miyazaki Y, Hisake K, Takaoka M, Morimoto S. Role of endothelin-1 and the ETA receptor in the maintenance of DOCA-salt induced hypertension. Br J Pharmacol. 1995;114:925–930.[Medline] [Order article via Infotrieve]
27. Schiffrin EL, Sventek P, Li JS, Turgeon A, Reudelhuber T. Antihypertensive effect of an endothelin receptor antagonist in DOCA-salt spontaneously hypertensive rats. Br J Pharmacol. 1995;115:1377–1381.[Medline] [Order article via Infotrieve]
28.
Bird JE, Moreland S, Waldron TL, Powell JR. Antihypertensive effects of a novel endothelin-A receptor antagonist. Hypertension. 1995;25:1191–1195.
29.
Chen WC, Chen CC. Signal transduction of arginine vasopressin-induced arachidonic acid release in H9c2 cardiac myoblasts: role of Ca2+ and the protein kinase C-dependent activation of p42 mitogen-activated protein kinase. Endocrinology. 1999;140:1639–1648.
30. Yoshizumi M, Kim S, Kagami S, Hamaguchi A, Tsuchiya K, Houchi H, Iwao H, Kido H, Tamaki T. Effect of endothelin-1 (1–31) on extracellular signal-regulated kinase and proliferation of human coronary artery smooth muscle cells. Br J Pharmacol. 1998;125:1019–1027.[Medline] [Order article via Infotrieve]
31.
Pucci ML, Miller KB, Dick LB, Guan H, Lin L, Nasjletti A. Vascular responsiveness to nitric oxide synthesis inhibition in hypertensive rats. Hypertension. 1994;23:744–751.
32. Orton TC, Parker GL. The effect of hypolipidemic agents on the hepatic microsomal drug-metabolizing enzyme system of the rat: induction of CYP-450 with specificity toward terminal hydroxylation of lauric acid. Drug Metab Dispos. 1982;10:110–115.[Abstract]
33.
Yin T, Sandhu G, Wolfgang CD, Burrier A, Webb RL, Rigel DF, Hai T, Whelan J. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem. 1997;272:19943–19950.
34.
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.
35. 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]
36. 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]
37.
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.
38.
Vojtek AB, Der CJ. Increasing complexity of the Ras signaling pathway. J Biol Chem. 1998;273:19925–19928.
39. Gibbs JB, Oliff A. The potential of farnesyltransferase inhibitors as cancer therapeutics. Annu Rev Pharmacol Toxicol. 1997;37:143–166.[Medline] [Order article via Infotrieve]
40. Selge H, Hall CE. Pathologic changes induced in various species by overdosage with DOCA. Arch Pathol. 1943;36:19–31.
41.
Owens GK, Schwartz SM. Alterations in vascular smooth muscle mass in spontaneously hypertensive rats: role of cellular hypertrophy, hyperploidy and hyperplasia. Circ Res. 1982;51:280–289.
42.
Owens GK, Schwartz SM. Vascular smooth muscle cell hypertrophy and hyperploidy in Goldblatt hypertensive rat. Circ Res. 1983;53:491–501.
43. Folkow B, Hallback M, Lundren Y, Sivertsson R, Weiss L. Importance of adaptive change in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats. Circ Res. 1973;32:2–16.
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