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Abstract
Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that angiotensin II–induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1−/− mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II–induced hypertension and associated pathophysiological changes. Moreover, 2,3′,4,5′-tetramethoxystilbene, which prevents both cytochrome P450 1B1–dependent and –independent components of angiotensin II–induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.
- angiotensin II
- cytochrome P450 1B1
- Cyp1b1−/− mice
- blood pressure
- cardiac and vascular hypertrophy
- vascular reactivity
- endothelial function
Angiotensin II (Ang II) is a major component of the mechanisms regulating cardiovascular homeostasis by maintaining vascular tone and salt and water balance.1 Ang II also activates cytosolic phospholipase A2 and releases arachidonic acid (AA) from phospholipids.2 AA is metabolized by cyclooxygenase into prostaglandins and thromboxane A2, by lipoxygenase into 5-, 12-, and 15-hydroxyeicosatetraenoic acids (HETEs), by cytochrome P450 (CYP) ω-hydroxylase into 20-HETE, and by epoxygenase into epoxyeicosatrienoic acids.3 Prostaglandins E2 and I2 and epoxyeicosatrienoic acids contribute to antihypertensive mechanisms,4,5 whereas prostaglandin precursor PGH2 and 20-HETE contribute to prohypertensive mechanisms.6–8 The balance between these antihypertensive and prohypertensive eicosanoids, together with other vasoactive agents, determines blood pressure levels. Products of AA generated via lipoxygenase (12-HETE) or CYP 4A (20-HETE) also promote vascular smooth muscle cell (VSMC) migration, proliferation, or hypertrophy by activating extracellular signal–regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK)9–13 and contribute to the vasoconstrictor action of Ang II.14 Moreover, inhibitors of lipoxygenase and CYP 4A minimize Ang II–dependent hypertension.6,15,16 Ang II and AA also stimulate production of reactive oxygen species (ROS) and activate c-Jun kinase and p38 MAPK but not ERK1/2 in VSMCs17–19 and Ang II–induced hypertension.20
In addition to cyclooxygenase, lipoxygenase, and CYP 4A, other CYP enzymes can also metabolize AA. CYP2 enzymes express mainly an epoxygenase activity, and CYP2B, 2C, and 2J are the major epoxygenases that metabolize AA into epoxyeicosatrienoic acids.8 CYP1 enzymes that metabolize xenobiotics can also metabolize endobiotics such as steroid hormones, retinoids, and fatty acids.21–24 CYP1A1 and CYP1B1 are expressed in several extrahepatic tissues, including cardiovascular tissues.25 CYP1A1-encoded enzymes are expressed in vascular endothelium and smooth muscle cells, with much higher levels of activity in endothelial cells, whereas CYP1B1 is highly expressed in VSMCs, with little expression in endothelial cells.26 However, shear stress upregulates mRNA and protein levels of CYP1A1 and CYP1B1 in endothelial cells.27 CYP1B1 can also metabolize AA in vitro mainly into midchain HETEs and to a lesser degree into terminal HETEs and epoxyeicosatrienoic acids.24 Moreover, bioactivation of procarcinogenic compounds such as aromatic hydrocarbons by CYP1B1 leads to formation of intermediates that form DNA adducts and polycyclic biphenyls which uncouple CYP1B1 resulting in the generation of ROS, lipid peroxidation, and DNA oxidation.28,29 Recently, however, we have shown that CYP1B1 mediates Ang II–induced VSMC migration and protein synthesis through ROS production.30 Therefore, it is possible that CYP1B1, through generation of AA metabolites and/or ROS, might activate ≥1 of the signaling molecules (eg, ERK1/2 or p38 MAPK) that contribute to Ang II–induced hypertension. To test this hypothesis, we examined the effects of 2,3′,4,5′-tetramethoxystilbene (TMS), a selective inhibitor of CYP1B1,31 on the development and maintenance of Ang II–induced hypertension in rats and the effects of Ang II in wild-type (Cyp1b1+/+) and CYP1B1 knockout (Cyp1b1−/−) mice. The results of this study demonstrate that CYP1B1 contributes to the development and maintenance of hypertension, most likely by increased generation of ROS, ERK1/2, and p38 MAPK activity; vascular hypertrophy; endothelial dysfunction; and increased vascular reactivity.
Methods
Please see the online Data Supplement at http://hyper.ahajournals.org.
Results
TMS Counteracts the Hypertensive Effect of Ang II in Rats
Ang II infusion increased MAP that was prevented by TMS; TMS alone did not alter MAP (Figure S1A, available in the online Data Supplement). In hypertensive rats injected with TMS, MAP returned to basal levels (Figure S1B). For each treatment, appropriate vehicles were administered, and no difference was observed (data not shown).
TMS Protects Against Cardiac Hypertrophy, Fibrosis, and Inflammation Associated With Ang II–Induced Hypertension in Rats
Ang II infusion increased heart:body weight (HW/BW) ratio and brain natriuretic peptide mRNA expression, indicators of cardiac hypertrophy. TMS alone had no effect on HW/BW ratio and brain natriuretic peptide mRNA level but minimized the increase in these parameters caused by Ang II (Table S1, available in the online Data Supplement). The increase in myofibroblasts, as indicated by α-smooth muscle actin staining in the myocardium, and ED-1 positive cells, an index of macrophages, in the perivascular space of the heart caused by Ang II was reduced by TMS (Figure S2).
TMS Decreases CYP1B1 Activity But Not Its Expression or Plasma Levels of 12- and 20-HETE
CYP1B1 protein expression was not altered in the aorta (Figure S3A) or heart (Figure S3B) after the various treatments. However, in animals treated with TMS, CYP1B1 activity in the aorta and heart was reduced. CYP1B1 activity was not increased in animals infused with Ang II but was reduced by concurrent treatment with TMS (Figure S3C and S3D). In hypertensive rats given TMS, CYP1B1 activity was decreased in the aorta and heart (Figure S4). Plasma levels of 12- and 20-HETE were not changed in the different treatment groups (Table S2).
TMS Prevents Increased Vascular Reactivity and Vascular Smooth Muscle Hypertrophy and Improves Endothelial Dysfunction in Ang II–Treated Rats
Ang II–induced hypertension was associated with an increased response of aorta (Figure S5A) and mesenteric (Figure S5B) and femoral (Figure S5C) arteries to phenylephrine (PE), endothelin 1 (ET-1), and vasopressin, as well as the media:lumen ratio of these vessels (Table S3); these increases were prevented in rats treated with TMS. In rats given TMS alone, responses of these vessels to the above agents and their media:lumen ratio were not altered (Figure S5 and Table S3, respectively). In hypertensive rats given TMS, both vascular reactivity and media:lumen ratio were reduced in all of the blood vessels studied (Figure S6 and Table S3, respectively).
Ang II infusion caused endothelial dysfunction in the aorta and femoral artery but not the mesenteric artery, as determined by the dilatory effect of acetylcholine (ACh) (Figure S7A). In animals infused with Ang II and given TMS, ACh- and sodium nitroprusside (SNP)–induced relaxations were not altered (Figure S7). After treatment with TMS to animals after they were made hypertensive with Ang II, ACh- and SNP-induced relaxations were not altered (Figure S8).
TMS Inhibits ROS Production, Activity, and Expression of NADPH Oxidase and ERK1/2 and p38 MAPK Activities in the Rat Aorta Caused by Ang II Infusion
ROS production, as determined by dihydroethidium (DHE) fluorescence, was increased in the aorta of animals infused with Ang II (Figure S9A and S9B). TMS treatment alone decreased ROS production in the aorta and abolished the increase caused by Ang II infusion (Figure S9A and S9B). To confirm the DHE fluorescence caused by the generation of 2-hydroxyethidium (2-OHE), as a specific indicator of superoxide production, we used a high-performance liquid chromatography method to separate 2-OHE formed from DHE generated in isolated aortic rings and measured using a fluorescence detector. As was observed with the DHE fluorescence, animals infused with Ang II showed a greater conversion of DHE to 2-OHE, which was inhibited with TMS (Figure S9C). TMS treatment alone had a minimal effect on basal conversion of DHE to 2-OHE (Figure S9C). ROS production was also decreased in animals made hypertensive and then given TMS, as determined by fluorescence microscopy after exposure of vessels to DHE (Figure S10). Expression of NADPH oxidase 1 (NOX 1), as measured by Western blot analysis (Figure S11A), and NADPH oxidase activity, as measured by a lucigenin-based luminescence assay (Figure S11B), were increased in the aorta of Ang II–infused animals but inhibited in animals treated with TMS. Expression of NOX 4 was not altered in any treatment group (Figure S11C).
Ang II is known to increase the activity of ERK1/2 and p38 MAPK in VSMCs, which contribute to hypertrophy and increased vascular reactivity. In this study, ERK1/2 and p38 MAPK activity, measured by phosphorylation of these kinases, were increased in the aorta of rats infused with Ang II that was attenuated in rats treated with TMS (Figure S12).
CYP1B1 Contributes to the Development of Ang II–Induced Hypertension in Mice
To further determine the contribution of CYP1B1 in the development of Ang II–induced hypertension, we examined the effect of Ang II in Cyp1b1−/− and Cyp1b1+/+ mice. Infusion of Ang II increased MAP in Cyp1b1+/+ and Cyp1b1−/− mice, but the increase was significantly less in Cyp1b1−/− than in Cyp1b1+/+ mice (Figure 1A). In Cyp1b1+/+ mice, TMS treatment alone had no effect on MAP, but the Ang II–induced increase in MAP was prevented by TMS (Figure 1B). The CYP1B1-independent component of Ang II–induced hypertension in Cyp1b1−/− mice was also abolished by TMS (Figure 1C).
Figure 1. CYP1B1 contributes to the development of Ang II–induced hypertension in mice. A, Cyp1b1+/+ and Cyp1b1−/− mice were infused with either Ang II (1000 μg/kg per day) or vehicle with miniosmotic pumps for 13 days, and blood pressure was measured by tail cuff every third day. B, Cyp1b1+/+ mice and (C) Cyp1b1−/− mice were infused with either Ang II (1000 μg/kg per day) or vehicle and given IP injections of the CYP1B1 inhibitor, TMS (300 μg/kg), every third day starting day 1 of the experiment, and blood pressure was measured every third day. *P<0.05 vehicle vs corresponding value from Ang II–treated animal; †P<0.05 Cyp1b1+/+ Ang II vs Cyp1b1−/− Ang II; #P<0.05 Cyp1b1+/+ Ang II vs Cyp1b1+/+ Ang II+TMS; ‡P<0.05 Cyp1b1−/− Ang II vs Cyp1b1−/− Ang II+TMS. n=4 for all experiments, and data are expressed as mean±SEM.
TMS and CYP1B1 Gene Disruption Reduce Cardiac Hypertrophy and CYP1B1 Activity in Ang II–Induced Hypertension in Mice
Infusion of Ang II increased HW/BW ratio in Cyp1b1+/+ and Cyp1b1−/− mice; however, the increase in HW/BW ratio was significantly less in Cyp1b1−/− mice. In both strains of mice, the increase in HW/BW ratio associated with Ang II was prevented by TMS (Table 1).
Table 1. TMS and Cyp1b1 Gene Disruption Reduce Cardiac Hypertrophy Associated With Ang II–Induced Hypertension in Mice
CYP1B1 activity in the heart and kidney of Cyp1b1−/− mice was inhibited (Figure S13A and S13B). Infusion of Ang II did not increase CYP1B1 activity in tissues from Cyp1b1−/− or Cyp1b1+/+ mice; however, CYP1B1 activity was further reduced by TMS in both strains of mice (Figure S13A and S13B). The remaining activity in Cyp1b1−/− mice could result from CYP1A1 activity detected by the assay. Cyp1b1−/− mice showed no expression of CYP1B1 in the heart, and infusion of Ang II did not alter CYP1B1 protein expression in the heart of Cyp1b1+/+ mice (Figure S13C).
Ang II–Induced Increase in Vascular Reactivity, and Hypertrophy and Endothelial Dysfunction Are Diminished in Cyp1b1−/− Mice
In Cyp1b1+/+ and Cyp1b1−/− mice, infusion of Ang II increased vascular reactivity of the aorta to PE and ET-1 and media:lumen ratio; these increases were significantly less in Cyp1b1−/− than in Cyp1b1+/+ mice (Figure 2 and Table 2, respectively). The increased vascular reactivity to PE and ET-1 and media:lumen ratio associated with Ang II in Cyp1b1+/+ mice and that remaining in Cyp1b1−/− mice was prevented by TMS; TMS alone had no effect on these parameters (Figure S14 and Table 2).
Figure 2. TMS and Cyp1b1 gene disruption reduce increased aortic response to vasoconstrictor agents associated with Ang II–induced hypertension in mice. Cyp1b1+/+ and Cyp1b1−/− mice were infused with either Ang II or vehicle for 13 days and given IP injections of TMS as described in the Figure 1 legend. Vascular reactivity was measured in the aorta as described in the Methods section. A and B, The response of aorta of Cyp1b1+/+ and Cyp1b1−/− mice infused with Ang II or vehicle to increasing concentrations of phenylephrine (PE) and endothelin 1 (ET-1). *P<0.05 vehicle vs corresponding value from Ang II–treated animal; †P<0.05 Cyp1b1+/+ Ang II vs Cyp1b1−/− Ang II. n=4 for all experiments, and data are expressed as mean±SEM.
Table 2. TMS and Cyp1b1 Gene Disruption Reduce Media:Lumen Ratio Associated With Ang II–Induced Hypertension in Mice
Ang II infusion resulted in endothelial dysfunction, as indicated by decreased relaxation to ACh in the aorta from Cyp1b1+/+ but not Cyp1b1−/− mice (Figure S15A). Endothelium-independent relaxation of aorta to SNP in Cyp1b1+/+ and Cyp1b1−/− mice remained unaltered in all of the treatment groups (Figure S15B). The decrease in ACh-induced relaxation of aorta from Cyp1b1+/+ mice infused with Ang II was prevented by TMS (Figure S15C); SNP-induced relaxation of the aorta was not altered (Figure S15D). In Cyp1b1−/− mice infused with Ang II, ACh- and SNP-induced relaxation of the aorta remained unaltered (Figure S15E and S15F, respectively).
Ang II–Induced Increase in ROS Production Is Diminished in Cyp1b1−/− Mice and Inhibited by TMS in Cyp1b1+/+ Mice
Infusion of Ang II in both Cyp1b1+/+ and Cyp1b1−/− mice increased aortic ROS production, as measured by fluorescence of 2-OHE generated after exposure of aorta to DHE, but the increase in fluorescence in Cyp1b1−/− mice was significantly less than that in Cyp1b1+/+ mice (Figure 3). In both Cyp1b1+/+ and Cyp1b1−/− mice infused with Ang II or its vehicle, TMS treatment decreased the intensity of fluorescence (Figure 3).
Figure 3. TMS and Cyp1b1 gene disruption reduce vascular oxidative stress associated with Ang II–induced hypertension in mice. Cyp1b1+/+ and Cyp1b1−/− mice were infused with either Ang II or vehicle for 13 days and given IP injections of TMS as described in the Figure 1 legend. ROS production was determined in aortic sections by DHE fluorescence as described in the Methods section. §P<0.05 Cyp1b1+/+ vehicle vs Cyp1b1−/− vehicle; *P<0.05 vehicle vs corresponding value from Ang II–treated animal; †P<0.05 Cyp1b1+/+ Ang II vs Cyp1b1−/− Ang II; ‡P<0.05 vehicle vs corresponding value from TMS-treated animal; #P<0.05 Ang II vs corresponding value from Ang II+TMS-treated animal. n=4 for all experiments, and data are expressed as mean±SEM.
Ang II–Induced Increase in Expression of NOX 1 and NADPH Oxidase Activity Is Diminished in the Heart of Cyp1b1−/− Mice
Ang II infusion increased expression of NOX 1 in the heart of Cyp1b1+/+ mice; this increase was significantly greater than that observed in Cyp1b1−/− mice (Figure S16A). In addition, NADPH oxidase activity was increased in the hearts of Cyp1b1+/+ and Cyp1b1−/− mice, but the increase in Cyp1b1−/− mice was significantly less than that in Cyp1b1+/+ mice (Figure S16B).
Discussion
This is the first study to demonstrate a novel mechanism whereby CYP1B1 contributes to development and maintenance of Ang II–induced hypertension and associated vascular hypertrophy, endothelial dysfunction, increased vascular reactivity to vasoconstrictor agents, cardiac hypertrophy, fibrosis and inflammation and generation of ROS, increased expression of NOX 1 and activities of NADPH oxidase, ERK1/2, and p38MAPK.
Our finding that TMS, a selective inhibitor of CYP1B1,31 decreased CYP1B1 activity in the rat aorta and heart prevented Ang II–induced increase in MAP and normalized the MAP raised by Ang II infusion and minimized the associated increase in (1) HW/BW ratio and the expression of brain natriuretic peptide mRNA in the left ventricle; (2) actin staining of myofibroblasts and accumulation of ED-1–positive cells in the myocardium; and (3) the response of the aorta and mesenteric and femoral arteries to PE, ET-1, vasopressin, and the media:lumen ratio of these vessels, suggests that CYP1B1 contributes to the development and maintenance of hypertension and cardiac hypertrophy, fibrosis and inflammation, and vascular reactivity and hypertrophy. Because TMS treatment also reduced CYP1B1 activity in the heart and aorta of vehicle-treated animals and Ang II infusion did not increase the activity or expression of CYP1B1, it appears to be constitutively active in these tissues as shown in VSMCs.30 Although TMS treatment prevented the development and maintenance of hypertension caused by Ang II in rats, it did not completely inhibit CYP1B1 activity in the aorta or heart; the remaining activity could result from CYP1A1 activity detected by our assay or a related enzyme. In cultured rat VSMCs that do not express CYP1A1, TMS blocks the activity of CYP1B1, as measured by our assay.30
Recombinant CYP1B1 can metabolize AAs in vitro into midchain and terminal HETEs, including 12- and 20-HETE.24 Both 12- and 20-HETE contribute to VSMC proliferation and/or hypertrophy and vascular contraction caused by Ang II, and 20-HETE increases reactivity of mesenteric arteries to PE from spontaneously hypertensive and Wistar-Kyoto rats.32 Therefore, it is possible that the increased vascular reactivity and hypertrophy caused by Ang II could result from increased production of eicosanoids, 12- and 20-HETE. However, this appears to be unlikely, because plasma levels of 12- and 20-HETE were not altered in rats treated with Ang II or TMS. In rat VSMCs, TMS or adenovirus CYP1B1 short hairpin RNA also do not alter AA metabolism into HETEs.30 The conversion of AA to 12- and 20-HETEs examined in the femoral arteries of rats treated with TMS was also not altered (our unpublished data).
In the present study, infusion of Ang II in rats caused endothelial dysfunction in the aorta and femoral artery, as indicated by attenuation of relaxation to ACh but not to SNP that acts directly on vascular smooth muscle. Inasmuch as loss of ACh-induced relaxation caused by Ang II infusion was restored by concurrent administration of TMS to rats, it appears that CYP1B1 participates in endothelial dysfunction in the aorta and femoral artery and may also contribute to increased vascular reactivity in Ang II–induced hypertension. Endothelium-dependent relaxation depends mainly on NO in larger arteries and on endothelium-derived hyperpolarizing factor(s) in small vessels.33 Chronic infusion of Ang II reduces NO-mediated relaxation in the aorta,34 whereas Ang II–infusion for 21 but not 14 days produces loss of the major component of relaxation dependent on endothelium-derived hyperpolarizing factor(s) and not the minor NO-dependent component of relaxation in the rat superior mesenteric artery.35 In our study, infusion of Ang II also failed to cause endothelial dysfunction in the small resistance mesenteric artery. From these observations, it follows that endothelial dysfunction in different vascular tissues depends on the duration of exposure to Ang II and that NO-dependent relaxation in larger vessels is more sensitive to Ang II and depends on CYP1B1 activity.
The endothelial dysfunction in different models of hypertension is in part attributed to the result of inactivation of NO by ROS.34 Therefore, in our study, restoration of endothelium-dependent relaxation to ACh in the aorta and femoral artery, produced by concurrent treatment with TMS in Ang II–infused rats, most likely results from decreased production of ROS generated via CYP1B1. Supporting this view was our demonstration that Ang II infusion increased aortic superoxide production and expression of NOX 1 and NADPH oxidase activity, which was prevented in the aorta of rats treated with TMS. Recently, we reported that Ang II–induced increase in ROS production in rat VSMCs is mediated by CYP1B1.30 Because Ang II is known to stimulate ROS production by activating NADPH oxidase and it has been implicated in Ang II–induced hypertension,17,36 it is possible that ROS and/or AA metabolites generated by CYP1B1, independent of HETEs, result in activation of NADPH oxidase. ROS have been reported to amplify their own production by activating NADPH oxidase, xanthine oxidase, increasing intracellular uptake of iron and/or uncoupling endothelial NO synthase.37 Further studies are required to determine the relationship between CYP1B1 and NADPH oxidase and other ROS-producing systems. Moreover, we cannot exclude the possibility of an additional direct effect of TMS on NADPH oxidase or other ROS-producing systems.
The increase in ROS production from AA via CYP1B1 by Ang II infusion could result in increased vascular reactivity and hypertrophy through activation of ERK1/2 and p38 MAPK, which are known to mediate Ang II–induced hypertrophy of cultured VSMCs.10,38 Supporting this view was our finding that infusion of Ang II increased aortic ERK1/2 and p38 MAPK activity that was attenuated by treatment with TMS. Moreover, we have shown that, in cultured rat VSMCs or in cells transduced with adenovirus CYP1B1 short hairpin RNA, Ang II– and AA-induced ERK1/2 and p38 MAPK activities are inhibited by TMS without alterations in expression of Ang II type 1 receptor or its coupling to G proteins.30
Further evidence that CYP1B1 contributes to the development of Ang II–induced hypertension and associated pathophysiological changes is derived from our studies in Cyp1b1−/− mice that do not express CYP1B1 protein. Our findings that the increase in MAP, HW/BW ratio, media:lumen ratio, the response to PE and ET-1, ROS production, and cardiac expression of NOX 1 and NADPH oxidase activity caused by Ang II infusion in Cyp1b1+/+ mice were significantly decreased in Cyp1b1−/− mice strongly support our findings in the rat treated with TMS that CYP1B1 contributes to Ang II–induced hypertension and associated pathophysiological changes. Our finding that endothelial function remained unaltered in Cyp1b1−/− mice indicates that CYP1B1 is required for aortic endothelial dysfunction associated with Ang II–induced hypertension. CYP1B1 activity, measured in the heart and kidney of Cyp1b1−/− mice, was reduced but not abolished and was further reduced by TMS. The remaining activity could result from CYP1A1 or other related enzyme(s), as mentioned above. Inasmuch as administration of TMS abolished Ang II–induced increase in blood pressure and all of the associated cardiovascular changes in Cyp1b1+/+ mice, as well as the CYP1B1-independent component of Ang II actions in Cyp1b1−/− mice, it appears that TMS exerts an additional protective effect against the deleterious effects of Ang II on the cardiovascular system. The mechanism of the protective effects of TMS against the CYP1B1-independent component of Ang II–induced hypertension and associated ROS generation and vascular changes, which could be attributed to its direct effect on ≥1 ROS-generating systems, remains to be determined.
Ang II–induced hypertension also depends on its actions in the kidney39 and central nervous system, and superoxides have been implicated in hypertension caused by central actions of Ang II.40 Recently, it has been shown that T cells (T-helper 17 cells), via generation of superoxides, participate in Ang II–induced hypertension.41 Another recent report shows that Ang II, by increasing RhoA activity via Jak2-induced phosphorylation of Rho exchange factor Arhgef1,42 results in increased vascular contraction and hypertension. Therefore, it is possible that CYP1B1 expressed in the kidney, brain,43 and lymphocytes,44 via ROS generation and/or increased RhoA activity, might also contribute to Ang II–induced hypertension. Alternatively, ≥1 of these mechanisms might contribute to the CYP1B1-independent and TMS-sensitive component of Ang II–induced hypertension and associated pathophysiological changes. Whether CYP1B1 directly or indirectly also contributes to hypertension caused by increased activity of the sympathetic nervous system also remains to be determined.
Perspectives
Increased activity of the renin-angiotensin system is a major contributing factor in the development of various vascular diseases, including hypertension. Further understanding of the mechanisms that are involved in Ang II–dependent hypertension would provide a rationale approach for the development of new therapeutic agents for the treatment of cardiovascular diseases. This study provides evidence for the first time that CYP1B1 contributes to Ang II–induced hypertension and associated pathophysiological changes, including increased ROS production, vascular reactivity, endothelial dysfunction, and vascular and cardiac hypertrophy. In preliminary experiments, we have found that CYP1B1 also contributes to desoxycorticosterone acetate/salt and Nω-nitro-l-arginine methyl ester hydrochloride–induced hypertension and to spontaneous hypertension in rats. Moreover, TMS, which prevents both CYP1B1-dependent and -independent components of Ang II–induced hypertension and associated pathophysiological changes, could be clinically useful for treating hypertension and other cardiovascular and related inflammatory diseases.
Acknowledgments
We thank Dr Bernd Meibohm and Josiah T. Ryman for assistance with the high-performance liquid chromatography experiment and Dr David L. Armbruster for editorial assistance.
Sources of Funding
The described project was supported by grant R01-19134-34 (to K.U.M.) from the National Institutes of Health, National Heart, Lung, and Blood Institute. B.L.J. was supported in part by a fellowship from the Neuroscience Institute, University of Tennessee Health Science Center. S.S.-F. was supported by the Scientific and Technical Research Council of Turkey.
Disclosures
None.
Footnotes
-
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute.
- Received April 7, 2010.
- Revision received April 25, 2010.
- Accepted August 6, 2010.
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