Published online before print November 24, 2003, doi: 10.1161/01.HYP.0000105110.12667.F8
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(Hypertension. 2004;43:117.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
ROS During the Acute Phase of Ang II Hypertension Participates in Cardiovascular MAPK Activation But Not Vasoconstriction
From the Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Correspondence to Shoji Kimura, MD, PhD, Department of Pharmacology, Kagawa University Medical School, 1750-1 Miki-cho, Kagawa 761-0793, Japan. E-mail kimura{at}kms.ac.jp
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Abstract |
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The relations among hypertensive response, oxidative stress, and mitogen-activated protein kinase (MAPK) in cardiovascular tissues have not been fully established. We investigated the involvement of reactive oxygen species on changes in the hemodynamics and cardiovascular MAPKs activities induced by acutely administered angiotensin II (Ang II) in conscious normotensive rats with or without treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol). Intravenous infusion of a pressor dose of Ang II rapidly increased mean arterial blood pressure (MBP) by 53±5 mm Hg. After a 30-minute treatment with Ang II, phosphorylated MAPKs (ERK1/2, JNK, p38) as well as thiobarbital reactive substances (T-BARS) were increased in the aorta and cardiac left ventricle. Tempol had no significant effect on the elevation of MBP elicited by Ang II; however, it dose-dependently suppressed the augmented phosphorylation of cardiovascular MAPKs and increased T-BARS levels in plasma and tissues induced by Ang II. An acutely administered pressor dose of phenylephrine, an
-adrenoceptor agonist, also showed tempol-sensitive cardiovascular MAPK activation and tempol-insensitive blood pressure elevation. These in vivo data indicate that acute administration of Ang II or phenylephrine provoked an increase in oxidative stress in the cardiovascular tissues leading to the activation of MAPKs, whether it was mediated by pressure overload or the direct action of these vasoconstrictors, and that oxidative stress might not have a major contribution to the acute hypertensive responses elicited by the vasoconstrictors.
Key Words: angiotensin II • adrenergic receptor agonists • oxidative stress • protein kinases • phosphorylation • rats
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Introduction |
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The importance of oxidative stress in the progression of atherosclerosis and hypertension is well documented.1–4 Previously, our laboratory demonstrated that vascular superoxide anion generation was increased in chronic Angiotensin (Ang) II–induced hypertensive rats.5 Studies have also shown that the development of hypertension seen in spontaneously hypertensive rats (SHR) was associated with a greater production of superoxide anions in vascular tissues.6,7 Although a correlation between reactive oxygen species (ROS) and chronic hypertension has become apparent,5–8 the role of ROS in the regulation of acute hypertensive response has not been characterized.
The mitogen-activated protein kinase (MAPK) pathway is a tyrosine kinase–dependent pathway normally stimulated by growth factors and cellular stress or inflammatory cytokines.9,10 There is increasing evidence that this pathway is involved in various cardiovascular disorders such as cardiac hypertrophy or atherosclerosis.11,12 The importance of extracellular signal-regulated kinase (ERK1/2) MAPK for maintaining high blood pressure has been revealed by using a specific inhibitor in chronically Ang II–infused rats.13 In cultured vascular smooth muscle cells (VSMC), Ang II rapidly stimulated phosphorylation of the MAPK family, ERK1/2, p38 and c-jun N-terminal kinase (JNK).14–16 These MAPK activations by Ang II were also shown in cardiac components, cardiomyocytes, and fibroblasts in culture. Some of these effects were redox-sensitive.17–20 Another Gq protein–coupled receptor stimulator, -adrenergic agonist, is also a strong MAPK activator in VSMC21 and cardiac myocytes.22,23 In addition to these in vitro studies, whole-body studies have clearly demonstrated rapid and transient augmentation of cardiac and vascular MAPK activities, indicating that Ang II and -adrenergic agonist stimulated MAPKs in a manner very similar to the in vitro observations.24,25 However, besides the direct receptor-mediated activation of MAPKs by these compounds, increases in afterload and shear stress must be considered in the in vivo state.26,27 Furthermore, although redox-sensitive MAPK activations have been shown in in vitro studies, it is still unknown whether ROS generated in the whole body and local tissues in response to acute hypertension in vivo really participate in the activation of cardiovascular MAPKs.
4-Hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) is a membrane-permeable superoxide dismutase (SOD) mimetic that exhibits potent antioxidant activity against superoxide as well as hydroxy radicals.28,29 We have demonstrated that tempol decreased vascular superoxide anion production and arterial blood pressure in conscious chronically Ang II–induced hypertensive rats in vivo.5 In the current study, with the use of tempol, we evaluated the role of ROS in the acute hypertensive responses and cardiovascular MAPK activities elicited by Ang II and an -adrenoceptor agonist, phenylephrine (Phe), in conscious rats and found tempol-sensitive MAPK activations in cardiovascular tissues without significant effects on the hemodynamic changes induced by these vasoconstrictors.
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Methods |
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Animal Preparation
Nine-week-old male Sprague-Dawley rats were used. Polyethylene catheters were implanted in the femoral artery for measurement of mean arterial blood pressure (MBP) and heart rate (HR) and in the femoral and carotid veins for the administration of isotonic saline, Ang II (Sigma), Phe (Wako Pure Chemical Industry Ltd), and/or AT1 receptor antagonist (CV11974; Takeda Chemical Industries Ltd), prazosin (Wako), tempol (Sigma), and 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (3-CP; Sigma), respectively. All rats were allowed to recover for 24 hours before the initiation of the experimental procedure, and all experiments were performed on conscious rats. The infusion rates of Ang II and Phe were 0.2 and 40 µg/kg per minute, respectively. CV11974, tempol and 3-CP were given at priming doses of 1, 30, and 30 µg/kg per minute, followed by infusion at rates of 0.1, 0.5, and 0.5 mg/kg per minute, respectively, which were started 5 minutes before the infusion of appropriate vasoconstrictors. Prazosin was given at a dose of 1 mg/kg, 5 minutes before the infusion of Phe. For dose-response studies, tempol was given at priming doses of 30, 10, and 3 mg/kg, followed by infusion at rates of 0.5, 0.167, and 0.05 mg/kg per minute, respectively. Blood was collected before and at 10, 20, and 30 minutes after the Ang II infusion for the measurement of thiobarbituric acid reactive substances (T-BARS) in the plasma. Thirty minutes after Ang II or Phe administration, rats were killed, and the left ventricle (LV) and aorta were removed. All tissue and plasma samples were quickly frozen in liquid nitrogen and stored at -80°C. All surgical and experimental procedures were performed according to the guidelines for the care and use of animals established by Kagawa Medical University.
Measurements of ERK1/2, p38, and JNK MAPKs Activities
Phosphorylated MAPKs in the aorta and LV were analyzed by Western blot, with the use of anti–phospho-ERK1/2, anti-p38, and anti-JNK antibodies (Cell Signaling Tech Inc), according to the method of Kyaw et al.30 Immunoreactive bands were visualized through the use of enhanced chemiluminescence and quantified by LAS-1000 plus (Fujifilm Co).
Measurements of T-BARS in Plasma, Aorta, and LV
T-BARS levels in the plasma, aorta, and LV were measured according to the method of Kikugawa et al.31 Briefly, the aorta and LV tissues were homogenized (5% wt/vol) in a solution containing 0.15 mol/L KCl and 0.02 mol/L Tris-HCl (pH 7.4). The homogenate or plasma was mixed with 15% trichloroacetic acid and 0.375% thiobarbituric acid. Butylated hydroxytoluene (0.01%) was added to the assay mixture to prevent autoxidation of the sample, and the mixture was heated at 100°C for 15 minutes. After cooling, the mixture was centrifuged at 3500 rpm for 20 minutes, and the absorbance of the organic phase was measured at 535 nm.
Statistical Analysis
Values are reported as mean±SEM. Statistical significance between more than 2 groups was tested by means of 2-way ANOVA followed by the Newman-Keuls test or unpaired 2-tailed Student t test as appropriate, and values of P<0.05 were considered to indicate statistical significance.
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Results |
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Effects of Ang II and Combined Treatment With CV11974, Tempol, or 3-CP on MBP and HR
The hemodynamic changes induced by acute intravenous administration of Ang II to conscious rats are shown inFigure 1. After the start of Ang II infusion, a rapid and significant increase in MBP by 53±5 mm Hg was observed within 3 minutes. HR was decreased by Ang II from 343±14 to 273±19 bpm in 3 minutes and then returned to the preinfused level within 10 minutes. The AT1 receptor antagonist CV11974 completely inhibited the hemodynamic changes induced by Ang II (Table). Tempol or 3-CP alone did not change the MBP and HR during the experimental period, and simultaneous treatments of these compounds had no significant effects on the hypertensive response induced by Ang II (Figure 1 and Table).
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Effects of CV11974, Tempol, and 3-CP on the Activation of Cardiovascular MAPKs Induced by Ang II
The phosphorylated levels of cardiovascular MAPKs for the Ang II–infused group are shown inFigure 2. Ang II infusion increased the phosphorylation of aortic ERK1/2, JNK, and p38 MAPKs compared with the saline-infused control rats (2.7-, 2.8-, and 2.6-fold increases, respectively). It also resulted in increases in the phosphorylation of ERK1/2, JNK, and p38 MAPKs (2.8-, 5.8-, and 2.5-fold increases, respectively) in the LV. CV11974 had no effect on the basal aortic and LV phosphorylated MAPK levels but abolished the Ang II–induced increases. Simultaneous treatment with tempol but not with 3-CP blunted the increases in phosphorylated MAPKs induced by Ang II in both the LV and aorta. Tempol or 3-CP alone did not affect the basal phosphorylated MAPK levels in these tissues.
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Effects of CV11974, Tempol, and 3-CP on Increases in T-BARS Levels Induced by Ang II in Plasma, Aorta, and LV
To clarify whether acute infusion of Ang II really provoked oxidative stress in conscious rats in vivo, the TBARS levels in the plasma, LV, and aorta were measured with or without treatment of tempol. The plasma concentration of T-BARS significantly increased within 10 minutes after the start of Ang II infusion, and this was maintained until 30 minutes (Figure 3A). As shown inFigure 3B, a 30-minute infusion of Ang II increased the tissue T-BARS contents in the aorta and LV by 44% and 60%, compared with the sham-operated rats, respectively. CV11974 and tempol but not 3-CP suppressed these increases in the T-BARS levels. None of these compounds alone affected the basal T-BARS levels in the plasma or tissues.
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Inhibitory Dose-Response Effect of Tempol on Ang II–Induced Cardiovascular MAPK Activation and Increases in T-BARS Levels
We next examined the dose dependency of tempol treatment on Ang II–induced cardiovascular MAPKs activation and increases in the plasma and tissue T-BARS levels. As shown inFigure 4A, in the aorta, low doses of tempol significantly suppressed p38 and JNK activation by Ang II. However, aortic ERK1/2 activation by Ang II was rather resistant to tempol treatment and only significantly suppressed by a highest dose of tempol. A similar pattern of tempol sensitivity was seen for the inhibition of MAPK activation in LV by Ang II.
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The increases in plasma and tissue T-BARS levels induced by Ang II were also suppressed by tempol treatment in a dose-dependent manner (Figure 4B).
Effects of Phe and Combined Treatment With Prazosin, Tempol, or 3-CP on MBP and HR
The hemodynamic changes induced by acute administration of Phe to conscious rats are shown inFigure 5. Intravenous Phe infusion increased MBP more rapidly than Ang II by 48±2 mm Hg and decreased HR from 353±11 to 220±21 bpm within 1 minute and maintained these levels until 30 minutes. Prazosin decreased MBP by 28 mm Hg and completely suppressed the vasopressor response of Phe infusion (Table). Tempol and 3-CP had no significant effects on the hemodynamic changes induced by Phe (Figure 5 andTable).
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Effects of Prazosin, Tempol, and 3-CP on Phe-Induced Activation of Cardiovascular MAPKs and Increases in T-BARS in Plasma and Tissues
Administration of Phe showed stronger effects than Ang II on the induction of phosphorylated cardiovascular MAPKs. Namely, phosphorylated ERK1/2, JNK, and p38 MAPKs were increased by 3.1-, 5.9-, and 3.2-fold in the aorta, respectively, and by 6.1-, 7.9-, and 3.7-fold in LV, respectively (Figure 6A). The T-BARS levels in the plasma, aorta, and LV were all increased by Phe infusion by 55%, 44%, and 86%, respectively (Figure 6B). Prazosin and tempol but not 3-CP blunted the increases in phosphorylated cardiovascular MAPKs and increases in T-BARS levels in the plasma and tissues (Figure 6,A and B).
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Discussion |
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In this study, we demonstrated that acute intravenous administration of Ang II and Phe increased the phosphorylation of the LV and/or aortic MAPKs in conscious normotensive rats, which was accompanied by increases in the T-BARS levels in the plasma and these tissues. The augmentations of phosphorylated MAPKs and T-BARS levels were inhibited by combined treatment with tempol. However, the hypertensive responses to these agents were not significantly affected by the simultaneous treatment with tempol. These results indicate that the increased oxidative stress evoked by these vasoconstrictors enhanced the phosphorylation of cardiovascular MAPKs but that the involvement of oxidative stress in the acute vasoconstrictor responses elicited by Ang II and Phe was limited.
Previously, our laboratory has shown that vascular superoxide anion generation increased in chronic Ang II–infused hypertensive rats, whereas tempol decreased not only the generation of vascular superoxide anions but also the peripheral vascular resistance, leading to a reduction in arterial blood pressure.5 In addition, as shown in the development of hypertension in SHR, high blood pressure was correlated with increased vascular superoxide anion generation.6,7 Therefore, in SHR and chronic Ang II–infused hypertensive rats, oxidative stress must play an important role in developing and maintaining high blood pressure.32 Tempol exhibits excellent cell permeability33,34 and could also effectively normalize blood pressure in SHR.34,35 In this study, we have shown for the first time that acute administration of Ang II to conscious normotensive rats increased the plasma and tissue T-BARS levels rapidly and that tempol but not 3-CP, a structurally related and inactive compound of tempol, blunted these effects, indicating that acutely administered Ang II enhanced lipid peroxidation in cardiovascular tissues. However, in this model of acutely hypertensive rats, we could not find significant inhibitory effects of simultaneous tempol treatment on the elevation of blood pressure induced by Ang II. In the acute hypertensive response to Ang II, stimulation of the IP3-Ca2+ system accounts for the initial effects of Ang II, namely the rapid development of vascular smooth muscle contraction.36 Thus, it was suggested that the in vivo mechanisms of developing and maintaining high peripheral vascular resistance in chronic Ang II–infused hypertensive rats were different from those of the acute hypertensive response to Ang II from the viewpoint of ROS sensitivity.
On the other hand, as shown in this study, the activation of MAPKs by Ang II was suppressed by simultaneous treatment with tempol but not with 3-CP, indicating that the increased ROS production in response to acute infusion of Ang II may lead to the augmented phosphorylation of cardiovascular MAPKs. Furthermore, it was found that among the MAPKs, the activations of JNK and p38 MAPKs were more sensitive to tempol treatment than that of ERK1/2 MAPK in both the aorta and LV, although high doses of tempol completely blunted all the increases in MAPK phosphorylation induced by Ang II. Thus, in the whole body as well as in in vitro studies,30,37 there may be different ROS-sensitive pathways for the activation of the cardiovascular MAPK family.
The enhanced oxidative stress might be caused by acute pressure overload on the tissues, since there is increasing evidence that stretching of cultured cells can stimulate superoxide production38–40 and activate MAPKs.41,42 The NAD(P)H oxidase system, present in cardiac and vascular tissues, is also a candidate for the source of the superoxide, and it is stimulated directly by Ang II treatment.38,43 According our results, it may be concluded that the activation of cardiovascular MAPKs by acute challenge with Ang II is ROS-sensitive, whether it is mediated by pressure overload or the direct action of Ang II.
We also investigated another Gq protein–coupled vasoconstrictor compound, Phe, to examine the role of oxidative stress in the regulation of cardiovascular MAPKs activities in conscious rats. Intravenous infusion of Phe resulted in a hypertensive response and activation of MAPKs in arterial walls.9 It was postulated that the activation of MAPKs was due to a direct effect of the elevated blood pressure on the arterial walls, or at least it was the primary stimulus. The increased oxidative stress induced by Phe also comes from the activated NAD(P)H oxidase system, since NAD(P)H oxidase appeared to be the intracellular source of the ROS shown in cultured cardiomyocytes in response to direct -adrenoreceptor stimulation.22 Similar to the case of Ang II, tempol but not 3-CP blunted the Phe-induced activation of cardiovascular MAPKs and increases in plasma and tissue T-BARS levels, supporting the hypothesis that whether through primary -adrenoreceptor stimulation or secondary pressure overload, ROS is a factor responsible for stimulating cardiovascular MAPK activity in response to Phe. Under basal conditions, -adrenoreceptors do not appear to contribute to cardiac and vascular MAPKs activation, since blockade of -adrenoreceptors had no significant effect on the basal phosphorylation of MAPKs in the tissues, despite a large reduction in MBP. This is also true for AT1 receptor blockade, as shown in this study.
It is generally accepted that the levels of phosphorylated MAPKs in cardiovascular tissues become normalized during long-term treatment with Ang II or other vasoconstrictors. However, reports have revealed that an acute treatment with a specific ERK-MAPK inhibitor after chronic treatment with Ang II reduced blood pressure.13 It was also demonstrated that the increased oxidative stress and enhanced MAPKs activities would activate transcriptional factors such as AP-1 and NF-
B and trigger gene expression.44–46 Therefore, there might be different mechanisms of contribution from activated MAPKs, even if their phosphorylation levels are not enhanced, during the development of cardiovascular remodeling under hypertension and atherosclerosis, which have high oxidative stress. It is of note that our present data do not reveal the source of the ROS mediating the MAPKs cascade. One of the major sources of ROS is the NAD(P)H oxidase system, and mitochondria are also a major source of superoxide generation in the cardiac and vascular tissues.40 Further investigation is necessary to understand the main source of the ROS in response to acute and chronic hypertension and the relations among ROS, MAPKs, and cardiovascular remodeling, including hypertension.
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Acknowledgments |
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This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.
Received September 10, 2003; first decision September 30, 2003; accepted October 17, 2003.
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G.-X. Zhang, S. Kimura, A. Nishiyama, T. Shokoji, M. Rahman, L. Yao, Y. Nagai, Y. Fujisawa, A. Miyatake, and Y. Abe Cardiac oxidative stress in acute and chronic isoproterenol-infused rats Cardiovasc Res, January 1, 2005; 65(1): 230 - 238. [Abstract] [Full Text] [PDF]
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