Role of NADH/NADPH Oxidase–Derived H2O2in Angiotensin II–Induced Vascular Hypertrophy

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

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Possible Role of NADPH Oxidase 4 in Angiotensin II-Induced Muscle Wasting in Mice

Frontiers in Physiology ◽

10.3389/fphys.2018.00340 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 6

Author(s):

Tomoyasu Kadoguchi ◽

Kazunori Shimada ◽

Hiroshi Koide ◽

Tetsuro Miyazaki ◽

Tomoyuki Shiozawa ◽

...

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Muscle Wasting ◽

Nadph Oxidase 4

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Role of PLD−PKCζ signaling axis in p47phox phosphorylation for activation of NADPH oxidase by angiotensin II in pulmonary artery smooth muscle cells

Cell Biology International ◽

10.1002/cbin.11145 ◽

2019 ◽

Vol 43 (6) ◽

pp. 678-694 ◽

Cited By ~ 3

Author(s):

Sajal Chakraborti ◽

Jaganmay Sarkar ◽

Tapati Chakraborti

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Pulmonary Artery ◽

Nadph Oxidase ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Signaling Axis ◽

Pulmonary Artery Smooth Muscle

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Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00408.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. H2364-H2372 ◽

Cited By ~ 51

Author(s):

Valentina Grishko ◽

Viktor Pastukh ◽

Viktoriya Solodushko ◽

Mark Gillespie ◽

Junichi Azuma ◽

...

Keyword(s):

Nitric Oxide ◽

Dna Damage ◽

Angiotensin Ii ◽

Nadph Oxidase ◽

Ventricular Remodeling ◽

Oxidase Inhibitor ◽

Neonatal Cardiomyocytes ◽

Diphenylene Iodonium ◽

Nitric Oxide Inhibitor

Angiotensin II contributes to ventricular remodeling by promoting both cardiac hypertrophy and apoptosis; however, the mechanism underlying the latter phenomenon is poorly understood. One possibility that has been advanced is that angiotensin II activates NADPH oxidase, generating free radicals that trigger apoptosis. In apparent support of this notion, it was found that angiotensin II-mediated apoptosis in the cardiomyocyte is blocked by the NADPH oxidase inhibitor diphenylene iodonium. However, three lines of evidence suggest that peroxynitrite, rather than superoxide, is responsible for angiotensin II-mediated DNA damage and apoptosis. First, the inducible nitric oxide inhibitor aminoguanidine prevents angiotensin II-induced DNA damage and apoptosis. Second, based on ligation-mediated PCR, the pattern of angiotensin II-induced DNA damage resembles peroxynitritemediated damage rather than damage caused by either superoxide or nitric oxide. Third, angiotensin II activates p53 through the phosphorylation of Ser15 and Ser20, residues that are commonly phosphorylated in response to DNA damage. It is proposed that angiotensin II promotes the oxidation of DNA, which in turn activates p53 to mediate apoptosis.

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138 Cell-specific role of NOX2 NADPH oxidase in development of angiotensin ii-induced cardiac fibrosis in vivo

Heart ◽

10.1136/heartjnl-2011-300198.138 ◽

2011 ◽

Vol 97 (Suppl 1) ◽

pp. A77-A78

Author(s):

S. Chaubey ◽

C. E. Murdoch ◽

A. Ivetic ◽

B. Yu ◽

D. Vanhoutte ◽

...

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Cardiac Fibrosis ◽

Specific Role

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Angiotensin-induced defects in renal oxygenation: role of oxidative stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00626.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. H22-H28 ◽

Cited By ~ 112

Author(s):

William J. Welch ◽

Jonathan Blau ◽

Hui Xie ◽

Tina Chabrashvili ◽

Christopher S. Wilcox

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Glass Electrode ◽

Ang Ii ◽

Renal Vasoconstriction ◽

Mrna And Protein Expression ◽

Renal Vascular ◽

Induced Defects ◽

Renal Oxygen

We tested the hypothesis that superoxide anion (O2−·) generated in the kidney by prolonged angiotensin II (ANG II) reduces renal cortical Po2 and the use of O2 for tubular sodium transport (TNa:QO2). Groups ( n = 8–11) of rats received angiotensin II (ANG II, 200 ng·kg−1·min−1 sc) or vehicle for 2 wk with concurrent infusions of a permeant nitroxide SOD mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol, 200 nmol·kg−1·min−1) or vehicle. Rats were studied under anesthesia with measurements of renal oxygen usage and Po2 in the cortex and tubules with a glass electrode. Compared with vehicle, ANG II increased mean arterial pressure (107 ± 4 vs. 146 ± 6 mmHg; P < 0.001), renal vascular resistance (42 ± 3 vs. 65 ± 7 mmHg·ml−1·min−1·100 g−1; P < 0.001), renal cortical NADPH oxidase activity (2.3 ± 0.2 vs. 3.6 ± 0.4 nmol O2−··min−1·mg−1 protein; P < 0.05), mRNA and protein expression for p22 phox (2.1- and 1.8-fold respectively; P < 0.05) and reduced the mRNA for extracellular (EC)-SOD (−1.8 fold; P < 0.05). ANG II reduced the Po2 in the proximal tubule (39 ± 1 vs. 34 ± 2 mmHg; P < 0.05) and throughout the cortex and reduced the TNa:QO2 (17 ± 1 vs. 9 ± 2 μmol/μmol; P < 0.001). Tempol blunted or prevented all these effects of ANG II. The effects of prolonged ANG II to cause hypertension, renal vasoconstriction, renal cortical hypoxia, and reduced efficiency of O2 usage for Na+ transport, activation of NADPH oxidase, increased expression of p22 phox, and reduced expression of EC-SOD can be ascribed to O2−· generation because they are prevented by an SOD mimetic.

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Role of the actin cytoskeleton in angiotensin II signaling in human vascular smooth muscle cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-006 ◽

2005 ◽

Vol 83 (1) ◽

pp. 91-97 ◽

Cited By ~ 21

Author(s):

Rhian M Touyz ◽

Guoying Yao ◽

Ernesto L Schiffrin

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle ◽

Nadph Oxidase ◽

Actin Cytoskeleton ◽

Cytochalasin B ◽

Ros Generation ◽

Ang Ii ◽

Ros Formation

Angiotensin II (Ang II) regulates vascular smooth muscle cell (VSMC) function by activating signaling cascades that promote vasoconstriction, growth, and inflammation. Subcellular mechanisms coordinating these processes are unclear. In the present study, we questioned the role of the actin cytoskeleton in Ang II mediated signaling through mitogen-activated protein (MAP) kinases and reactive oxygen species (ROS) in VSMCs. Human VSMCs were studied. Cells were exposed to Ang II (10–7 mol/L) in the absence and presence of cytochalasin B (10–6 mol/L, 60 min), which disrupts the actin cytoskeleton. Phosphorylation of p38MAP kinase, JNK, and ERK1/2 was assessed by immuno blotting. ROS generation was measured using the fluoroprobe chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (4 µmol/L). Interaction between the cytoskeleton and NADPH oxidase was determined by evaluating the presence of p47phox in the Triton X-100 insoluble membrane fraction. Ang II significantly increased phosphorylation of p38MAP kinase, JNK, and ERK1/2 (two- to threefold above control, p < 0.05). Cytochalasin B pretreatment attenuated p38MAP kinase and JNK effects (p < 0.05) without altering ERK1/2 phosphorylation. ROS formation, which was increased in Ang II stimulated cells, was significantly reduced by cytochalasin B (p < 0.01). p47phox, critically involved in NADPH oxidase activation, colocalized with the actin cytoskeleton in Ang II stimulated cells. Our data demonstrate that Ang II mediated ROS formation and activation of p38MAP kinase and JNK, but not ERK1/2, involves the actin cytoskeleton in VSMCs. In addition, Ang II promotes interaction between actin and p47phox. These data indicate that the cytoskeleton is involved in differential MAP kinase signaling and ROS generation by Ang II in VSMCs. Together, these studies suggest that the cytoskeleton may be a central point of crosstalk in growth- and redox-signaling pathways by Ang II, which may be important in the regulation of VSMC function.Key words: superoxide, NADPH oxidase, p38MAP kinase, JNK, ERK1/2.

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