(Hypertension. 1997;29:790-795.)
© 1997 American Heart Association, Inc.
Articles |
Heme Oxygenase-1 Is Regulated by Angiotensin II in Rat Vascular Smooth Muscle Cells
the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Ga.
Correspondence to Nobukazu Ishizaka, Emory University Division of Cardiology, 319 Woodruff Memorial Bldg, 1639 Pierce Dr, Atlanta, GA 30322. E-mail nishizaka@emory.edu
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Abstract |
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Recently, heme oxygenase-1 (HO-1) has been shown to be present in vascular smooth muscle cells. In the present study, we examined the effect of angiotensin II (Ang II) on HO-1 in rat vascular smooth muscle cells. After treatment with 100 nmol/L Ang II, HO-1 mRNA levels were decreased, with a nadir at 2 hours (39±9% of the control level, P<.01). This downregulation was completely blocked by the Ang II type 1 receptor antagonist losartan. Western blot analysis showed that HO-1 protein is also significantly downregulated, with a nadir at 4 hours (52±6% of the control level, P<.01). Heme oxygenase activity was also significantly decreased at 4 hours (control, 0.35±0.86 nmol bilirubin/mg per hour; Ang II, 0.10±0.06). This downregulation was observed in serum-starved cells to a similar extent as in serum-supplemented cells. Inhibitors of protein kinase C, lipoxygenase, cyclooxygenase, cytochrome P450 monooxygenase, and phospholipase A2 did not block this downregulation. However, this effect was not observed in the absence of calcium and presence of EGTA (2 mmol/L). Furthermore, a 2-hour incubation with calcium ionophore or arginine vasopressin decreased HO-1 mRNA levels, suggesting that an increase of intracellular calcium mediates the downregulation. In conclusion, Ang II decreases HO-1 mRNA in a calcium-dependent manner in vascular smooth muscle cells, which may provide a novel mechanism for the modulation of vascular tone and oxidative stress.
Key Words: angiotensin • muscle, smooth, vascular • antioxidants
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Introduction |
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Heme oxygenase-1 (HO-1) is an inducible form of heme oxygenase (HO) that hydrolyzes approximately 1% of the heme in blood to equimolar carbon monoxide1 2 3 and biliverdin, which is subsequently converted by biliverdin reductase to bilirubin.1 In vitro and in vivo studies show that HO-1 is present in vascular smooth muscle cells (VSMCs).4 Carbon monoxide, like nitric oxide, activates soluble guanylate cyclase, leading to an increase in cGMP production.5 6 As the carbon monoxide generated by HO in various organs may be released into local7 and systemic circulations, HO-1 regulation may be important for the modulation of vascular tone.8
Recent animal studies suggest a link between HO-1 activity and systemic blood pressure. Increased HO activity induced by treatment with tin chloride9 or heme arginate10 lowered the blood pressure of spontaneously hypertensive rats. Zinc deuteroporphyrin 2,4-bis glycol or zinc protoporphyrin IX, specific inhibitors of HO, significantly increased the blood pressure of Sprague-Dawley rats.11 However, it is yet to be determined if these antihypertensive effects are mediated by HO present in the vessel wall or in other organs, because HO-1 is widely distributed in various organs, such as brain, liver, and kidney.12 In addition, induction of HO-1 leads to depletion of cytochrome P450 monooxygenase, whose products, hydroxyeicosatetraenoic acids, contribute to hypertension by promoting vasoconstriction and sodium retention.10 Therefore, it is possible that the antihypertensive effect is mediated through a decrease in P450 levels.
Induction of HO-1 is also important in counteracting oxidative stress. HO catabolizes and subsequently decreases the cellular heme, which is a pro-oxidant, and elevates the level of bilirubin, which is an antioxidant.13 Through the generation of ferrous iron, induction of HO-1 is accompanied by increased ferritin expression and activity,14 15 which exerts an antioxidant effect by chelating the free iron that is essential for the Haber-Weiss reaction, which generates hydroxyl radical and initiates biological damage.16 HO-1 is induced by various oxidants, including superoxide anion, UV irradiation, and hydrogen peroxide.17 In vivo14 and in vitro18 studies have shown that HO-1 induced by oxidative stress may act protectively as an antioxidant. Previously, we have shown that angiotensin II (Ang II) induces an increase in superoxide anion generation by activating an NADH/NADPH oxidase in rat VSMCs19 and aortas from rats made hypertensive by continuous Ang II infusion.20 In the present study, our purpose was to examine Ang II–induced HO-1 regulation in rat VSMCs.
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Methods |
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Materials
Rat HO-1 cDNA was a kind gift from Dr S. Shibahara, Tohoku (Japan) University School of Medicine. Losartan was a kind gift from Dr R.D. Smith (DuPont-Merck, Wilmington, Del). TRI reagent was purchased from Molecular Research Center, and Ang II, dibucaine hydrochloride, indomethacin, and Dulbecco's modified Eagle's medium (DMEM) were purchased from Sigma Chemical Co. SKF-525A and 5,8,11,14-eicosatetraynoic acid were purchased from BioMol. GF 109203X was purchased from LC Laboratories; polyclonal antibody against rat HO-1 from StressGen Biotechnologies Corp; [32P]dCTP from DuPont-NEN; Magna NT nylon membrane from Stratagene; and Biospin P30 columns from Bio-Rad. Immobilon-P transfer membranes were purchased from Millipore Corp and Prime-It II probe labeling kits and the ECL Western blotting detection system from Amersham Life Sciences. Penicillin, streptomycin, glutamine, and calf serum were from GIBCO Life Technologies.
Cell Culture
VSMCs were isolated from the thoracic aorta of male Sprague-Dawley rats by enzymatic digestion as described previously.21 Cells were grown in DMEM supplemented with 10% calf serum, 2 mmol/L glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin and were passaged twice a week by harvesting with trypsin/EDTA and seeding into 80-cm flasks. For experiments, cells between passage levels 6 and 15 were seeded into 60- or 100-mm dishes, fed every other day, and used at confluence. In some experiments, VSMCs were incubated in serum-free medium for 48 hours before use. For studies on the effect of Ca2+ on HO-1 expression, cells were incubated in balanced salt solution (BSS) (mmol/L: HEPES 20 [adjusted to pH 7.4 with Tris base], NaCl 130, KCl 5, MgCl2 1, CaCl2 1.5, and glucose 10) for 15 minutes before the addition of Ang II. To remove extracellular calcium and prevent the intracellular calcium transient in response to Ang II, we added 2 mmol/L EGTA to calcium-free BSS.
RNA Isolation and Northern Blot Analysis
Total RNA was extracted from confluent VSMCs with the TRI reagent as described previously.22 Equal amounts of total RNA were subjected to electrophoresis in a 1.0% agarose minigel containing 6.5% formaldehyde, and RNA was transferred to a nylon membrane. After UV cross-linking, membranes were prehybridized at 42°C for 2 to 5 hours in 1 mol/L NaCl, 50 mmol/L Tris, 5x Denhardt's solution, 50% formamide, 0.5% sodium dodecyl sulfate (SDS), and 100 µg/mL sheared and denatured salmon sperm DNA. The rat HO-1 cDNA was labeled with [
-32P]dCTP in a standard random primed reaction, and unincorporated cDNA was removed on a Biospin P30 column. The hybridization reaction was performed overnight with 32P-labeled probe in 0.5% SDS. Blots were autoradiographed for 1 to 2 days at -80°C. For quantification, autoradiograms were scanned with an imaging densitometer with the use of the Molecular Analyst software (Bio-Rad Laboratories). Band density was normalized to the intensity of ethidium bromide–stained 28S and 18S ribosomal RNA after transfer to the membrane.
Protein Purification and Western Blot Analysis
Cells grown on 100-mm dishes were washed three times with ice-cold phosphate-buffered saline, and 1 mL lysis buffer (50 mmol/L HEPES, 5 mmol/L EDTA, 50 mmol/L NaCl, 1% Triton X-100, pH 7.5) with protease inhibitors (10 µg/mL aprotinin, 0.1 mmol/L phenylmethylsulfonyl fluoride, and 10 µg/mL leupeptin) was added to each dish. Samples were then agitated for 1 hour at 4°C. After 30 minutes of centrifugation at 4°C at 12 000g, the precipitated unsolubilized fraction was discarded. Protein concentration in the supernatant was determined by the Bradford microassay. Samples were then loaded onto 9% to 12% SDS–polyacrylamide gels and subsequently blotted onto PVDF membranes (Immobilon-P). Membranes were blocked with phosphate-buffered saline containing 3% bovine serum albumin and 0.1% sodium azide for 1 hour at 37°C. HO-1 protein expression was assessed with a polyclonal antibody against rat HO-1 at a 1:500 dilution. The ECL Western blotting system was used for detection.
Assay of HO Activity
VSMCs were dounce homogenized in 200 mmol/L phosphate buffer and centrifuged at 18 800g at 4°C for 10 minutes. The supernatant was removed and recentrifuged at 100 000g at 4°C for 60 minutes, and the precipitated microsomal fraction was suspended in 100 mmol/L potassium phosphate buffer (pH 7.4). Biliverdin reductase was crudely purified by the method of Tenhunen et al.4 HO activity was assayed according to the method of Yoshida et al.23 Reaction mixtures consisted of (final volume, 1 mL) 100 µmol potassium phosphate (pH 7.4), 15 nmol hemin, 300 µg bovine serum albumin, 1 mg purified biliverdin reductase, and 0.4 mg microsomal fraction of rat aortas. The reaction was allowed to proceed for 60 minutes at 37°C in the dark in a shaking water bath and was stopped by placing the test tube on ice. The incubation mixture was then scanned with a dual-beam scanning spectrophotometer (Perkin-Elmer Lambda 2S), and the amount of bilirubin formed was evaluated as the difference between absorbance at 464 and 530 nm, using an extinction coefficient of 40 mmol/L per centimeter.6 Protein in the microsomal preparations was determined by the method of Lowry et al.24
Statistical Analysis
Data are expressed as mean±SE. ANOVA followed by a multiple comparison test was performed on initial data before expression as a percentage of control. A value of P<.05 was considered statistically significant.
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Results |
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HO-1 mRNA and Protein Levels After Ang II Stimulation
VSMCs were stimulated with 100 nmol/L Ang II for 1 to 24 hours. Ang II decreased HO-1 mRNA levels as early as 1 hour, with a nadir at 2 hours (Fig 1
). HO-1 mRNA levels started to recover 4 hours after Ang II stimulation and returned to near control levels by 16 hours. A small decrease was again observed at 24 hours. The mRNA downregulation at 2 hours was dose dependent (Fig 2), with a threshold of 1 nmol/L and maximal effect at 100 nmol/L. This response was completely blocked by the specific Ang II type 1 receptor antagonist losartan (Ang II, 41±6% of control [P<.05]; losartan, 104±7% of control [P=NS]; Ang II plus losartan, 115±11% of control [P=NS]) (Fig 3). Western blot analysis demonstrated that the HO-1 protein level was also significantly decreased from 2 to 8 hours after Ang II addition (Fig 4). There was no significant difference in HO-1 protein level at 24 hours (data not shown). Importantly, HO activity 4 hours after Ang II addition was also significantly decreased (Fig 5).
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Serum Independence of Ang II–Induced HO-1 mRNA Regulation
In a preliminary experiment, we found that steady-state HO-1 mRNA levels were lower in cells that had been serum starved for 48 hours than in serum-supplemented cells. To determine whether Ang II–induced mRNA downregulation is serum dependent, we serum starved VSMCs for 48 hours and treated them with Ang II for 2 or 16 hours. As shown in Fig 6, Ang II–induced downregulation was observed in serum-starved cells to a similar extent as in serum-supplemented cells, indicating that Ang II–induced HO-1 mRNA downregulation is a serum-independent phenomenon. These data also indicate that Ang II exerts a negative regulation regardless of the basal level of expression.
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To verify that HO-1 mRNA levels are not already maximally induced, we exposed VSMCs to two known inducers of HO-1, hydrogen peroxide and hemin. As shown in Fig 7, hydrogen peroxide (100 to 400 µmol/L) potently induced HO-1 in the presence of serum (twofold to fourfold over control). Similarly, in serum-starved cells, hemin (12 µmol/L) increased HO-1 expression 2 to 4 hours after its addition to the culture medium. Thus, HO-1 mRNA is subject to both positive and negative regulation in VSMCs.
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Mechanism of Ang II–Induced HO-1 mRNA Downregulation
To examine the pathway leading to Ang II–induced HO-1 mRNA downregulation, we tested the effect of inhibitors of several major signaling pathways: calcium, protein kinase C, phospholipase A2, arachidonic metabolites, and superoxide. The cytochrome P450 monooxygenase inhibitor SKF-525A (25 µmol/L), the cyclooxygenase inhibitor indomethacin (10 µmol/L), the isomorphic arachidonic acid inhibitor 5,8,11,14-eicosatetraynoic acid (50 µmol/L), the phospholipase A2 inhibitor dibucaine (25 µmol/L), the protein kinase C inhibitor GF 109203X (3 µmol/L) (Fig 8), and the membrane-permeable nonenzymatic superoxide scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (10 mmol/L) (data not shown) did not have any effect on Ang II–induced HO-1 mRNA downregulation at 2 hours. These concentrations of inhibitors have been previously shown to effectively block the target pathways in VSMCs.4 21 22 23 Removal of intracellular calcium, however, blocked Ang II–induced downregulation of HO-1 mRNA. For these experiments, 15 minutes before Ang II stimulation, the medium was changed from DMEM to either BSS with calcium or BSS without calcium containing the calcium chelator EGTA (2 mmol/L). The Ang II–induced Ca2+ transient was markedly reduced, and sustained Ca2+ influx was abolished under the latter condition (data not shown). In calcium-deprived cells, HO-1 mRNA downregulation was completely inhibited (Fig 9a). These results suggest that Ca2+ mobilization mediates HO-1 mRNA downregulation. As further confirmation, we tested the effect of ionomycin (15 µmol/L), a calcium ionophore, and arginine vasopressin (100 nmol/L), another calcium-mobilizing hormone, on HO-1 mRNA levels. As shown in Fig 9b, both ionomycin and arginine vasopressin downregulated HO-1 mRNA to a similar extent as Ang II.
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Discussion |
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HO-1 has recently been shown to be expressed in VSMCs and regulated by hypoxia; however, little is known about HO regulation in VSMCs by vasoactive agents. In the present study, we showed that Ang II downregulates HO-1 mRNA, protein, and activity in rat VSMCs in a serum-independent and calcium-dependent manner. Although HO-1 is known to be induced by various agents, our findings provide some of the first evidence that HO-1 can also be regulated negatively.
The observations that HO-1 mRNA downregulation depended on the Ang II dose and was blocked by an Ang II type 1 receptor antagonist indicate that this is truly an Ang II–mediated effect. Although the HO-1 mRNA level was lower in serum-starved VSMCs, Ang II–induced downregulation was observed to a similar extent, indicating that Ang II–induced HO-1 downregulation is not due to blockade of the effect of some other factors in the serum. Furthermore, it does not appear to require activation of phospholipase A2, protein kinase C, or arachidonic acid metabolism because inhibitors of these pathways had no effect on HO-1 mRNA levels. However, the mechanism underlying downregulation does appear to involve calcium. Removal of extracellular calcium prevented Ang II–induced HO-1 downregulation, whereas calcium-mobilizing agents promoted downregulation. It has been reported that in human diploid fibroblasts, the prostaglandin A2–induced increase of intracellular Ca2+ leads to an increased HO-1 mRNA level by stabilization of HO-1 mRNA.25 Thus, the role of intracellular calcium in HO-1 regulation may be cell type specific.
The finding that Ang II decreased HO-1 mRNA levels in this study was rather unexpected. HO-1 has been shown to be induced by oxidative stress in various cell types, and Ang II causes a delayed generation of superoxide19 and hydrogen peroxide26 in VSMCs. In preliminary studies, we found that exogenous xanthine/xanthine oxidase and high concentrations of hydrogen peroxide increased HO-1 mRNA in VSMCs. However, low concentrations of hydrogen peroxide (0.3 µmol/L) decreased HO-1 mRNA as early as 1 hour after stimulation (N.I., K.K.G., unpublished data, 1996). Therefore, the effect of reactive oxygen species on HO-1 regulation in VSMCs may depend on the type and amount of generated reactive oxygen species.
In the vascular system, HO-1 has several potential roles. First, HO generates carbon monoxide, which has been shown to increase cGMP concentration in VSMCs,5 6 leading to relaxation. As cytochrome P450 levels are regulated by the availability of cellular heme, stimulation of HO activity may be accompanied by a parallel decrease of activity of cytochrome P450 monooxygenase,10 leading to a reduction in 20-hydroxyeicosatetraenoic acid, a vasoconstrictor.27 Therefore, Ang II–induced HO downregulation may lead to an augmentation of vasoconstriction by Ang II in vivo. Second, HO-1 acts as an antioxidant by generating bilirubin, increasing ferritin expression, and decreasing cellular heme.28 We have previously shown that Ang II increases superoxide production in vitro and in vivo by activating the NADH/NADPH oxidase20 and that generated superoxide is an important determinant of blood pressure in rats.29 These observations suggest that reduction of the antioxidant capability of the vessel wall by HO downregulation may lead to the augmentation of oxidative stress induced by Ang II. Finally, carbon monoxide generated by HO has been recognized as a putative neurotransmitter in the brain, like nitric oxide.30 Recently, it has been demonstrated that carbon monoxide released from VSMCs has paracrine effects and increases endothelin-1 and platelet-derived growth factor B in endothelial cells,31 suggesting that it also plays an important role in signal transduction. It is therefore also possible that Ang II–induced HO-1 regulation may have physiological effects on endothelial as well as smooth muscle cells.
In conclusion, Ang II decreases HO-1 mRNA, protein, and activity in VSMCs in a serum-independent, calcium-dependent manner. Ang II–stimulated HO-1 regulation may have important roles in modulating Ang II–induced oxidative stress in VSMCs and possibly in modulating vascular tone in vivo.
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Acknowledgments |
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This work was supported by National Institutes of Health grant HL-38206. We thank Dr R. Wayne Alexander for helpful discussions and Barbara Merchant-Bailey for excellent editorial assistance.
Received June 26, 1996;
first decision August 2, 1996;
first decision September 10, 1996;
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