Angiotensin II–Dependent Superoxide
Effects on Hypertension and Vascular Dysfunction
Angiotensin (Ang) II generates reactive oxygen species (ROS) by activation of Ang II type 1 receptors (AT1Rs). The resulting ROS mediates many of the actions of Ang II, including constriction of vascular smooth muscles, increased systemic blood pressure (BP), endothelial dysfunction, vascular remodeling, and sodium retention. Ang II has its greatest effect on superoxide anion (O2−), which may be an important signaling element of the hypertensive rats and other deleterious actions of Ang II. The mechanisms of ROS actions are not fully understood, yet effective antioxidant therapy often attenuates hypertension and other vascular effects of Ang II. Currently many studies use Ang II–infused animal models to investigate the role of ROS and interacting systems, not only on hypertension, but endothelial dysfunction, renal disease, heart disease, and other pathologies. This review focuses on the recent reports of Ang II–generated ROS and how it impacts hypertension and its vascular consequences.
Mechanism of Ang II Generation of O2−
Superoxides are formed by several oxidases and oxygenases and incomplete mitochondrial oxidative phosphorylation. The major source of O2− that impacts the vasculature and systemic BP is reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, which is abundantly expressed in vascular smooth muscle cells. Five isoforms of NADPH oxidase (Nox) have been identified in animals: Nox1 to Nox5, with Nox1, Nox2, and Nox4 expressed in vascular cells. Nox isoforms are composed of 2 to 5 subunits: 2 membrane-bound subunits, gp91phox and p22phox, and cytosolic subunits p47phox, p67phox, and Rac-1 (reviewed in Mehta and Griendling1). Ang II upregulates several subunits of NADPH oxidase; however, most evidence suggests that assembly of NADPH oxidase onto cell membranes is initiated by Rac-1, which is activated by Ang II binding to AT1R. However, alternate pathways continue to be explored. O2− generated by Nox is metabolized by superoxide dismutases (SOD) to form hydrogen peroxide (H2O2) or is scavenged by NO forming peroxynitrite. In addition, H2O2 is subsequently further reduced by catalase or glutathione peroxidase (Gpx). Interaction with these important metabolic pathways also determines the physiological effects of Ang II–generated O2−.
Transfection studies have linked Ang II with Nox isoforms. Nox1 and Nox2, as well as isoforms of p47phox and p67phox, NoxO1, and NoxA1 were transfected into cultured human embryonic kidney (HEK293) cells before Ang II exposure. Ang II increased activity of both Nox1 and Nox2, which was linked to intermediates Gα(q/11), phospholipase C-β, and protein kinase C.2 Maximal activity of Nox1 required NoxO1 and NoxA1, and Nox2 required p47phox and p67phox. Ang II effects on Nox2 were more predominant and required additional pathways, including phosphatidylinositol 3-kinase and Rac1, which confirms earlier studies.3
Signaling by Ang II to NADPH oxidase may also require the extracellular signaling-regulated kinase 1/2 mitogen-activated protein kinase pathways. In aortas harvested from Ang II–infused rats, O2−, extracellular signaling-regulated kinase 1/2 phosphorylation, and spontaneous tone were enhanced compared with control aortas. Specific inhibitors to mitogen-activated protein kinase/extracellular signaling-regulated kinase 1/2 reduced all of these effects. This suggests that the vasoconstriction associated with O2− derived from Ang II stimulation requires this important signaling process.4
The epithelial transcription factor-1 may also be part of the signaling process in Ang II–stimulated O2− production. O2− was lower in the thoracic aorta from epithelial transcription factor-1 (−/−) mice treated with Ang II than in wild-type tissue. In cultured human aortic smooth muscle cells, small interfering RNA to epithelial transcription factor-1 reduced O2− production and induction of p47phox by Ang II, confirming the in vivo results.5
BP Effects of Ang II-O2−
Although several Nox isoforms are involved in the generation of Ang II–dependent O2−, their role in the development of Ang II–dependent hypertension is less clear. Many studies have linked Ang II with vascular NAPDH oxidase based on inhibition by apocynin. However, a recent study showed that apocynin requires activation by myeloperoxidase to inhibit NAPDH oxidase. Myeloperoxidase is expressed in leukocytes but not in cultured vascular cells, suggesting that studies that have identified vascular Nox-dependent effects of Ang II based solely on the use of apocynin may need to be reconsidered.6 Yet, apocynin is an effective antioxidant and remains useful in identifying links between Ang II and O2−.
Further complicating this issue are recent studies using more specific genetic tools, such as single gene-deficient mouse models that have shown conflicting results. Separate reports show that Nox-1 or gp91phox knockout mice have similar BP but differ in responses to Ang II. Matsuno et al7 showed that Ang II infusion increased BP less in Nox1 knockout mice than in wild-type mice. However, in Nox1 knockout mice crossbred with transgenic mice expressing human renin (TTRhRen), which had high circulating Ang II, BP was similar to control mice.8
Conversely, overexpression of Nox increases BP responses to Ang II. When Nox2 was overexpressed in mice, acute and chronic infusion of Ang II increased BP more in transgenic mice compared with wild-type mice.9 Similarly, Nox-1 overexpression lead to greater increases in BP, O2− production, and smooth muscle hypertrophy compared with control mice.10 In addition, Tempol partially attenuated the increases in BP, O2−, and hypertrophy.10
These conflicting results may be because of differences in study designs comparing acute and chronic reductions of Nox. In Ang II–infused studies, the acute or short-term role of O2− in the development of hypertension has been shown in multiple studies, whereas compensation of the loss of O2− in chronic lifetime genetic models may mask its role. Alternately, high Ang II over a lifetime can increase BP and subsequent end-organ damage by other mechanisms, independent of O2−.
Using a different molecular strategy, Modlinger et al11 showed that reduction of p22phox, a subunit of multiple Nox isoforms, by small interfering RNA ameliorated Ang II–dependent increased BP. The Ang II–dependent hypertension, measured by radiotelemetry, was diminished by injection of small interfering RNA directed to p22phox in adult rats. The small interfering RNA–treated rats also had lower levels of isoprostane excretion.11
Another consideration is the effect of hypertension on O2− production, independent of Ang II. Other forms of hypertension, such as high salt intake or deoxycorticosterone infusions, also increase O2−.12,13 However, the studies cited above with Ang II infusion resulting in high circulating Ang II sufficient to increase BP show that BP was reduced by targeting Nox sources of O2− or O2− scavenging.8–11 Relevant to this issue is the study by Jalil et al,14 who showed that Brown Norway rats have elevated angiotensin-converting enzyme and circulating Ang II without hypertension. However, O2− production was higher in aorta from Brown Norway rats compared with those from the control Lewis rats and was substantially reduced by candesartan, an AT1R antagonist. This observation suggests that Ang II–linked O2− is not dependent on increased BP.14
Ang II-O2− Effects in the Heart
Cardiac hypertrophy generated by Ang II–dependent hypertension may also be because of increased O2−. Kobayashi et al15 studied the effects of carbon monoxide (CO) because it reduces O2− and may ameliorate the pro-oxidant effects of Ang II. In Ang II–infused mice, CO administered for 2 hours per day attenuated the rise in BP and left ventricular hypertrophy compared with Ang II controls. Multiple parameters of ROS were also reduced by CO treatment. Hydralazine, used as a control that did not alter CO, lowered BP in Ang II–treated mice but was less effective in reducing left ventricular hypertrophy and ROS. These authors conclude that CO acts via reduction in Ang II–dependent NADPH oxidase activity.
To examine the mechanism of cardiac hypertrophy, Ang II was exposed to primary rat cardiomyocytes.16 Ang II increased Rac1 activation, O2− production, and cell size, which were blocked by adenoviral introduction of dominant-negative Rac1 and CuZn-SOD and by small interfering RNA directed to Nox2. These results suggest that Ang II activation of Nox2 contributes to cardiac hypertrophy.
In an interesting study that suggests an important protective role of Ang II–generated O2−, cardiac damage after ischemia/reperfusion was attenuated by Ang II preconditioning.17 This appears to be mediated by both mitochondrial and NADPH oxidase–generated O2−, because the reduced infarct size was abolished by inhibition of both sources. In addition, the expression of NAPDH oxidase subunits and activity of NADPH oxidase were attenuated by Ang II preconditioning, suggesting that mitochondrial ROS are stimulated by cytosolic oxidases.
Not all of the recent studies have confirmed that Nox is linked to Ang II damage. Touyz et al18 showed that chronic Ang II–dependent cardiac hypertrophy was not altered in gp91phox (Nox1) knockout mice.
Vascular Effects of Ang II-O2−
Several recent studies have linked the endothelial dysfunction, inflammation, and excess vasoconstriction of Ang II to NAPDH oxidase and other sources of O2−. In the low renin model of Dahl salt-sensitive hypertension, reduction of gp91phox with gp91phox-tat reduced ROS production, improved endothelium-dependent relaxation, and lowered inflammatory precursors, without a significant effect on BP.19
Results from a model of Ang II–dependent hypertension generated by overexpression of the mouse renin transgene in rats suggest that vascular injury is mediated by increased O2− production.20 In these transgenic rats with substantially elevated Ang II, endothelial dysfunction, inflammation, insulin resistance, and vascular NADPH oxidase were all increased. Treatment with valsartan, an AT1R antagonist, or Tempol, a SOD mimetic, attenuated all of the parameters. However, in this model of malignant hypertension, Tempol did not have a significant effect on BP, whereas valsartan normalized BP.
Aortic dissection and aneurysm formation are additional consequences of endothelial dysfunction during hypertension. Seven days of Ang II infusion induced aortic dissection in 23% of wild-type mice but only 4% of Nox1-deficient mice.21 This study was particularly interesting because norepinephrine failed to generate aortic dissection, confirming the selective role of Ang II on NADPH oxidase.
Ang II also induces abdominal aortic aneurysms. To test the role of O2−, abdominal aortic aneurysms were assessed in apolipoprotein E (apoE; −/−) mice and crossbred apoE(−/−) and p47phox(−/−) mice, after 4 weeks of Ang II infusion. Ang II induced abdominal aortic aneurysm in 90% of apoE(−/−) mice but only 16% of apoE(−/−)/p47phox(−/−) mice. In addition, the Ang II pressor response was lower in apoE(−/−)/p47phox(−/−) mice compared with apoE(−/−) mice. As seen above, norepinephrine infusion did not generate abdominal aortic aneurysm or elevated O2−.22
Most studies have shown that NADPH oxidase is the major source of Ang II–dependent ROS; however, the mitochondrion is also a major source of O2−. Mitochondrial O2− was increased by Ang II in rat vascular smooth muscle cells and in the rat aorta. However, inhibition of mitochondria O2− by a specific ATP-sensitive potassium channel blocker had no effect on calcium mobilization in rat vascular smooth muscle cells or altered BP in Ang II–infused rats.23 These data suggest that Ang II–derived O2− sufficient to alter vascular tone and hypertension is independent of mitochondrial O2−, which confirms earlier work identifying NADPH oxidase as the major source.
Vascular injury caused by Ang II could be because of increased apoptosis. In the rat carotid artery and in cultured endothelial cells, Ang II and H2O2 increased indices of apoptosis and isoprostane production, a marker of O2−. Specific inhibition of AT1R reduced apoptosis and isoprostane production.24
AT1R blockers also reduced atherosclerosis and NADPH oxidase activity in apoE knockout mice, with less modest effects in female mice. The addition of estrogen (17-β estradiol) enhanced the antiatherosclerotic actions of olmesartan via its effects on O2− production.25 These data suggest that estrogen provides additional protection against excess O2−.
Vascular hypertrophy and aortic O2− production in mice are increased after 2 weeks of Ang II infusion. However, in mice in which catalase has been overexpressed only in vascular smooth muscle, thus reducing vascular H2O2 levels, hypertrophy was substantially attenuated.26 BP was not different in catalase-overexpressed mice.
Gpx metabolizes H2O2, providing vascular protection against this ROS. Carotid arteries from Gpx(−/−) mice were less responsive to relaxation induced by acetylcholine, an endothelium-dependent agonist, than wild-type arteries.27 In vitro exposure to Ang II also impaired relaxation to acetylcholine in arteries from Gpx(−/−) mice, whereas Ang II had no effect on arteries from Gpx-transgenic mice. This suggests that H2O2 mediates Ang II–induced endothelial dysfunction and that, under normal conditions, Gpx protects the vessels.
Ang II stimulates multiple inflammatory pathways; however, a recent study suggests that interleukin (IL)-6 is required for maximal O2− production in vessels. Carotid arteries from IL-6–deficient mice had less hypertrophy and endothelial dysfunction compared with wild-type tissue. Stimulation of vascular superoxide and IL-6 by Ang II was absent in IL-6(−/−) mice.28
Conversely, Ang II induces IL-6 via mineralocorticoid receptors in humans and may be independent of O2−. Human subjects were infused for 3 hours with low doses of Ang II, which increased plasma IL-6, but not after treatment with spironolactone. Spironolactone had no effect on Ang II stimulation of F2-isoprostanes, suggesting that this intervention did not alter O2− production.29
Neural Effects of Ang II-O2−
Hypertension is also linked to increased brain levels of Ang II, which mediates its effects partially via O2− and intracellular Ca++ changes. To examine this relationship, neuroblastoma cells were exposed to Ang II, which increased voltage-sensitive intracellular Ca++. This effect was attenuated by overexpression of CuZnSOD in these cells, which increased O2− scavenging, and by expression of the dominant-negative isoform of Rac1, preventing formation of NAPDH oxidase by Ang II.30
Similar roles for Ang II and O2− have been explored in the nuclear tractus solitarius, which is an important site for cardiovascular regulation by the brain. Suppression of NADPH oxidase in the nuclear tractus solitarius by transfection of adenoviral vectors for dominant-negative Rac-1 reduced Ang II–dependent BP by 20 to 30 mm Hg.31 This supports and confirms earlier studies in the aorta and kidney on the critical role of Rac-1 signaling in the stimulation of NADPH oxidase.32 Changes in Ca++ currents in the brain are also regulated by Ang II and, therefore, may require O2−. In a study using isolated nuclear tractus solitarius, Nox2 was required to show increased O2− production and enhanced Ca++ current in response to Ang II.33 This pathway was linked to protein kinase C, because specific inhibition also suppressed Ca++ responses to Ang II.
The β-1 receptor antagonist nebivolol has vasodilating and antioxidant properties. In Ang II–dependent hypertensive rats, nebivolol prevented vascular endothelial dysfunction, reduced O2− production, and enhanced bioavailable NO.34 This powerful antioxidant effect of nebivolol is related to its ability to prevent the assembly of NAPDH oxidase, demonstrated in cultured cells.
Sympathetic-initiated vasoconstriction in exercising muscle is attenuated by locally produced NO. However, in Ang II–infused rats, sympathetic, stimulation of femoral conductance was greater compared with control responses and was attenuated by the O2− scavenger Tempol. This suggests that, during high Ang II conditions, increased O2− activity leads to greater vasoconstriction in exercising muscle.35
Ang II-O2− in the Kidney
The kidney is a rich source of NADPH oxidase, which is stimulated by Ang II and linked to renal vasoconstriction, renal failure, and tubular function. Ang II increased DNA damage assessed in pig kidney cells (LLC-PK1) 6- to 15-fold. This was prevented by AT1R but not by Ang II type 2 receptor blockers. The antioxidants N-acetylcysteine and α-tocopherol also attenuated the effects of Ang II.36
The increase in NADPH oxidase by Ang II also impacts podocyte function, increasing inflammation and reducing filtration, further contributing to renal-based hypertension. In the renin transgenic rat, with high circulating Ang II, oxidative stress was attenuated by statin treatment resulting in less podocyte damage.37 In addition to their cholesterol-lowering effects, statins also inhibit Rac1 and Nox-dependent O2−.
In a model of slowly developing hypertension created by infusion of a low dose of Ang II, mice deficient of extracellular SOD (EC-SOD) had similar increases in MAP compared with wild-type mice. Ang II increased O2− production, renal expression of NADPH oxidase, and renal vascular resistance. This result suggests that EC-SOD is not a major defense against overproduction of superoxide. However, intracellular SOD in the kidney was upregulated by Ang II, compensating for the lack of EC-SOD.38
Conversely, a high dose of Ang II, which increased BP within 24 hours, had greater effects in EC-SOD knockout mice. In mesenteric resistance vessels, Ang II reduced endothelium-dependent vasodilation, as expected. Ang II caused paradoxical increases in endothelium-dependent vasodilation, and the authors suggest that increased CuZn-SOD activity in the aorta compensated for the lack of EC-SOD.39
Increased Ang II–dependent O2− may also alter renal function, possibly contributing to the elevation in BP. In Ang II–infused hypertensive rats, acute Tempol injections increased renal blood flow, glomular filtration rate, and Na excretion,40 whereas long-term Tempol treatment had no effect on renal function, measured at the end of a 2-week treatment period.41
In stroke-prone spontaneously hypertensive rats, renal expression of glutathione S-transferase μ type 1 (Gstm1) is 4-fold lower than Wistar-Kyoto rats, which may contribute to oxidative stress in these rats. Gstm1 is a major defense enzyme against excess O2− production, and the authors suggest that it may represent a novel candidate for hypertension-associated oxidative stress.42
Interactions With Other Vasoactive Systems
Stimulation of O2− by Ang II can alter other vasoactive systems, and several recent studies have expanded our knowledge of these potentially important interactions. Cyclooxygenases generate several vasoactive prostaglandins and may promote the formation of ROS. Infusion of Ang II in rats increased BP, oxidative stress, and cyclooxygenase-2 (COX-2) expression in the aorta and heart.43 Selective inhibition of COX-2 attenuated the hypertension and oxidative stress, whereas nonselective inflammatory inhibitors had no effect. In the kidney, COX-2 may also be regulated by O2− from Ang II-NADPH oxidase. COX-2 expression in the renal cortex of Dahl salt-sensitive rats on a high-salt intake was increased by 2-fold. Inhibition of AT1R by daily candesartan treatment restored normal COX-2 expression in Dahl salt-sensitive rats.44
However, COX-1 may be involved in endothelial dysfunction associated with Ang II–induced hypertension. In mesenteric arteries from Ang II–infused mice, the acetylcholine-induced relaxation was enhanced by a COX-1 inhibitor and by a thromboxane-prostanoid receptor antagonist.45 These effects were prevented by apocynin, suggesting that the effects of Ang II to increase COX-1 activity are mediated by NADPH oxidase. Increased COX-1 activity generates thromboxane that increased arterial tone, leading to endothelial dysfunction during Ang II infusion.
The kinin receptor B1 mediates vasodilation and participates in the regulation of vascular tone during hypertension. Ang II infusion for 2 weeks induced B1 receptor in the rat aorta, but this was prevented by cotreatment with apocynin.46 More importantly, apocynin did not lower the BP induced by Ang II. This suggests that AT1R activation stimulates B1 receptor induction, but only via NADPH oxidase, rather than increased BP.
Endothelin is a potent vasoactive hormone, which acts on 2 distinct receptors (endothelin A and B) and can increase vascular tone. Plasma endothelin levels are often increased by Ang II. Spontaneously hypertensive rat, a model of oxidative stress, has higher plasma endothelin levels, which may contribute to the high BP in this strain. To test the role of Ang II on oxidative stress and endothelin, spontaneously hypertensive rats and normotensive rats were treated with captopril for 15 days. BPs, markers of oxidant stress and endothelin levels, were reduced in spontaneously hypertensive rats but not in normotensive rats by captopril, suggesting that Ang II stimulation of endothelin is mediated by O2−.47
Endothelin may also be linked to Ang II signaling in cardiomyocytes. In isolated cardiomyocytes, short-term exposure to Ang II increased positive inotropic effects, measured by sarcomere shortening, increased O2− production, and increased endothelin levels.48 These effects could be blocked by AT1R blockers, antioxidants, or the endothelin A–selective blocker BQ-123. This study suggests that O2− activates endothelin A without having effects on endothelin formation.
Ang II also stimulates endothelin in the adventitia, which may contribute to vascular remodeling associated with hypertension. To examine the possible role of O2−, cultured mouse adventitial fibroblasts were exposed to Ang II and multiple redox or endothelin inhibitors.49 Ang II increased endothelin and collagen expression, but NADPH oxidase inhibitors and BQ123.43 attenuated this effect.
These selected new studies show that O2− generated by Ang II may stimulate other vasoactive systems and that these potential interactions are underappreciated.
There has been substantial progress on understanding the relationship among Ang II, AT1R activation, and NADPH oxidase production of O2− over the last 2 to 3 years. Ang II-derived O2− is recognized as an important signaling component of the classical effects of Ang II. In addition to its contribution to various pathologies, there is emerging evidence that O2− mediates normal physiology or can even be protective. The prohypertensive and provasoconstrictive mechanisms of O2− actions remain less clear. As new information emerges, we will learn how Ang II mediates many of its multiple functions via the release of ROS. This new information may lead to the development of antioxidant therapies that will complement Ang II antagonists in the treatment of hypertension and related vascular diseases.
Sources of Funding
The research of W.J.W. is supported by National Institutes of Health grants DK072183, DK36079, and DK4699501 (National Institute of Diabetes and Digestive and Kidney Diseases) and HL089583 and HL68686 (National Heart, Lung, and Blood Institute).
- Received March 6, 2008.
- Revision received March 17, 2008.
- Accepted April 22, 2008.
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