Distinct Effects of N-Acetylcysteine and Nitric Oxide on Angiotensin II-induced Epidermal Growth Factor Receptor Phosphorylation and Intracellular Ca2+ Levels

Wang, Biao; Yu, Xijie; Cohen, Richard A.; Brecher, Peter

doi:10.1074/jbc.275.16.12223

Cited by 67 publications

(41 citation statements)

References 27 publications

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“…Ang II has been shown to induce ERK 1/2 activation by both Ca 2ϩ /c-Src-dependent and -independent EGFR transactivation. 18,34,35 Our findings indicate that, in adult CFs, neither the EGFR nor c-Src is involved in signal transduction between the Ang II receptor and ERK 1/2, which distinguishes adult CFs from both neonatal CFs and VSMCs, which use EGFR transactivation.…”

Section: Discussionmentioning

confidence: 93%

Angiotensin II-Induced Extracellular Signal-Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase Cδ and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

et al. 2008

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Abstract-Angiotensin II (Ang II)-induced proliferation of cardiac fibroblasts is a major contributing factor to the pathogenesis of cardiac fibrosis. Ang II activates extracellular signal-regulated kinase (ERK) 1/2 to induce cardiac fibroblast proliferation, but the signaling pathways leading to ERK 1/2 activation have not been elucidated in these cells.The goal of the current study was to identify the intracellular mediators of Ang II-induced ERK 1/2 activation in adult rat cardiac fibroblasts. We determined that 100 nmol/L of Ang II-induced ERK 1/2 phosphorylation is inhibited by simultaneous chelation of cytosolic calcium and downregulation of protein kinase C (PKC) by phorbol ester or by the specific PKC␦ inhibitor rottlerin, as well as PKC␦ small interfering RNA, but not by inhibition of 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetate, phorbol ester, rottlerin, or PKC␦ small interfering RNA alone. We also found that Ang II does not transactivate the epidermal growth factor receptor in adult cardiac fibroblasts, because pretreatment with 1 mol/L of AG 1478 did not significantly inhibit [ 3 H]-thymidine incorporation or ERK 1/2 activation. In addition, immunoprecipitation of the epidermal growth factor receptor demonstrated no significant Ang II-induced phosphorylation of tyrosine residues. Inhibition of phosphatidylinositide 3-kinase, PKC, and src tyrosine kinase had no effect on Ang II-induced ERK 1/2 activation. Collectively, these data demonstrate that Ang II does not transactivate the epidermal growth factor receptor in adult rat cardiac fibroblasts to activate ERK 1/2, a common pathway described in vascular smooth muscle and other cell types, but rather occurs via activation of distinct parallel signaling pathways mechanistically controlled by intracellular Ca

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Section: Discussionmentioning

confidence: 93%

Angiotensin II-Induced Extracellular Signal-Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase Cδ and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

et al. 2008

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“…29,30 Pu et al 29 demonstrated that ROS activated Src through selective phosphorylation at tyrosine 416 in NIH3T3 cells. Wang et al 31 showed that NAC inhibited Src phosphorylation at tyrosine 416 by Ang II in cardiac fibroblasts. Mukhin et al 32 mapped the major point of intersection to ROS to upstream of or at the level of Src in the Gi␤␥3 Src33 ERK pathway using 5-HT1A receptor-transfected CHO cells.…”

Section: Discussionmentioning

confidence: 99%

ERK and p38 MAPK, but not NF-κB, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts

Sano

Fukuda

Satô

et al. 2001

Circulation Research

277

200

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Abstract-We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II-induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II-induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II-induced IL-6 expression. Because we observed that exogenous H 2 O 2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H 2 O 2 were compared. Ang II, as well as exogenous H 2 O 2 , activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous H 2 O 2 , however, Ang II did not influence phosphorylation and degradation of IB-␣/␤ or nuclear translocation of p65, nor did it increase NF-B promoter activity. PD98059 and SB203580 inhibited Ang II-induced IL-6 expression. Truncation and mutational analysis of the IL-6 gene promoter showed that CRE was an important cis-element in Ang II-induced IL-6 gene expression. NF-B-binding site was important for the basal expression of IL-6, but was not activated by Ang II. Ang II phosphorylated CREB through the ERK and p38 MAPK pathway in a ROS-sensitive manner. Collectively, these data indicated that Ang II stimulated ROS production via the AT1 receptor and NADH/NADPH oxidase, and that these ROS mediated activation of MAPKs, which culminated in IL-6 gene expression through a CRE-dependent, but not NF-B-dependent, pathway in cardiac fibroblasts. Key Words: angiotensin II Ⅲ interleukin-6 Ⅲ reactive oxygen species Ⅲ mitogen-activated protein kinase Ⅲ cardiac fibroblast C linical, experimental, and genetic data have demonstrated that the renin angiotensin system is linked to the pathogenesis of a variety of cardiac diseases. Expression of angiotensin II (Ang II), the key effector molecule of the renin angiotensin system, is increased under various pathophysiological conditions and stimulates cardiomyocyte hypertrophy and interstitial fibrosis coinciding with accumulation of extracellular matrix. Recent reports had shown that Ang II stimulates membrane-bound NAD(P)H oxidase, which generates reactive oxygen species (ROS) in a variety of nonphagocytic cells. 1 ROS may act as a second messenger that regulates various intracellular signal transduction cascades and the activity of various transcription factors. NF-B and AP-1 are the best characterized transcription factors to be influenced by the cellular oxidation-reduction (redox) state. 2,3 The primary target of activation of NF-B by ROS appears to be the phosphorylation and subsequent degradation of IB. 4 Another well-characterized redox sensitive signali...

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“…In addition, this receptor was shown to mediate responses that are normally activated by tyrosine kinase-linked receptors as exemplified by those for EGF and PDGF. The transactivation of these two growth factor receptors by angiotensin II is mediated by ROS and inhibited by antioxidants such as N-acetylcysteine (212,246,458,607). Preliminary evidence suggests that angiotensin II-mediated transactivation of the EGF receptor involves the intermittant activation of the Src family kinase p60 c-src by hydrogen peroxide (591), which can directly activate p60 c-src in mouse fibroblasts (4; see sect.…”

Section: A Role Of Ros In Receptor-mediated Signaling Pathways: the mentioning

confidence: 99%

Free Radicals in the Physiological Control of Cell Function

Dröge

2002

Physiological Reviews

8,364

5,836

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At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish “redox homeostasis.” Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman ( J Gerontol 11: 298–300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.

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Distinct Effects of N-Acetylcysteine and Nitric Oxide on Angiotensin II-induced Epidermal Growth Factor Receptor Phosphorylation and Intracellular Ca2+ Levels

Cited by 67 publications

References 27 publications

Angiotensin II-Induced Extracellular Signal-Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase Cδ and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

Angiotensin II-Induced Extracellular Signal-Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase Cδ and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

ERK and p38 MAPK, but not NF-κB, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts

Free Radicals in the Physiological Control of Cell Function

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