Apocynin attenuates pressure overload-induced cardiac hypertrophy in rats by reducing levels of reactive oxygen species

2010 ◽  
Vol 88 (7) ◽  
pp. 745-752 ◽  
Author(s):  
Jinjun Liu ◽  
Juan Zhou ◽  
Wenjiao An ◽  
Yuanxi Lin ◽  
Yubai Yang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Ang Ii ◽  
Body Weight Ratio ◽  
Local Expression

It has been shown that angiotensin II (Ang II) is involved in cardiac remodeling mediated by NADPH oxidase-dependent reactive oxygen species (ROS). Accordingly, NADPH oxidase-dependent ROS may play a role in cardiac hypertrophy induced by pressure overload. In the present study, we sought to determine whether inhibition of NADPH oxidase prevents cardiac hypertrophy. After abdominal aorta banding to induce cardiac hypertrophy, rats were treated for 8 weeks with apocynin (Apo) or captopril (Cap). Measures of cardiac hypertrophy were evaluated. Treatment with Cap or Apo reduced the left ventricle / body weight ratio (LV/BW), LV transnuclear myocyte diameter, and atrial natriuretic factor (ANF) mRNA expression relative to those of untreated rats subjected to aorta banding. The activity of NADPH oxidase and the ROS levels were decreased in treated animals. Cap, but not Apo, decreased Ang II levels and inhibited expression of p22phox and p67phox in LVs. In conclusion, local expression of Ang II appears to contribute to pressure overload-induced cardiac hypertrophy by upregulating NADPH oxidase expression and promoting ROS synthesis. Inhibition of NADPH oxidase and elimination of ROS may prevent or repair damage due to cardiac hypertrophy.

scholarly journals Ca 2+ -Dependent NOX5 (NADPH Oxidase 5) Exaggerates Cardiac Hypertrophy Through Reactive Oxygen Species Production

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 827-838 ◽  
Author(s):  
Guo-Jun Zhao ◽  
Chang-Ling Zhao ◽  
Shan Ouyang ◽  
Ke-Qiong Deng ◽  
Lihua Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Reactive Oxygen ◽  
Contractile Dysfunction ◽  
Oxygen Species ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Nadph Oxidase 5

NOX5 (NADPH oxidase 5) is a homolog of the gp91 phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca 2+ -sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes ( Nppa , Nppb , and Myh7 ) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca 2+ -regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.

Increased Generation of Vascular Reactive Oxygen Species by Ang II Is Mediated Via Src-Dependent Pathways in Essential Hypertension.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 685-685
Author(s):  
Rhian M Touyz ◽  
Ernesto L Schiffrin
Keyword(s):  
Reactive Oxygen Species ◽  
Essential Hypertension ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Leucine Incorporation ◽  
Oxygen Species ◽  
Ang Ii ◽  
Growth Responses ◽  
Hypertensive Patients ◽  
In Cells

42 We tested the hypothesis that augmented Ang II-induced vascular smooth muscle cell (VSMC) growth in human hypertension is mediated via Src-dependent pathways that generate reactive oxygen species (ROS). VSMCs from arteries of normotensive and hypertensive subjects were studied. Production of ROS was measured by fluorescence digital imaging using dichlorofluorescin diacetate (6 μM). The roles of Src and NADH/NADPH oxidase were assessed with the specific inhibitors, PP2 (10 μM) and diphenylene iodinium (DPI) (10 μM) respectively. c-Src phosphorylation was determined by western blot and kinase activity was assessed by measuring enolase phosphorylation. Ang II increased DCFDA fluorescence. This effect was inhibited by catalase, indicating that the signal was derived predominantly from H 2 O 2 . Ang II increased H 2 O 2 production within 40 minutes. Responses were greater (p<0.05) in cells from hypertensive patients (E max =82±nM) than normotensive subjects (E max = 67±nM). DPI and PP2, but not PP3 (inactive analogue) attenuated (p<0.05) Ang II-induced H 2 O 2 production. PP2 effects were greater in cells from hypertensive patients (delta H 2 O 2 , 28±5nM) vs controls (delta H 2 O 2 , 16±2nM). Ang II increased c-Src phosphorylation and activity, with responses 3-4 fold higher in hypertensives. DPI and PP2 (p<0.01) attenuated Ang II-induced DNA and protein synthesis, as measured by 3 H-thymidine and 3 H-leucine incorporation respectively. Growth responses in hypertensive patients were normalized by PP2. In VSMCs from hypertensive patients, Ang II-induced generation of ROS and growth are augmented. These effects are mediated, in part, by Src-dependent, NADH/NADPH oxidase-dependent cascades. Thus increased Src activity may be an upstream modulator of redox-sensitive pathways that regulate vascular growth and remodeling in essential hypertension.

scholarly journals Hypoxia-inducible Factor-1 Activation in Nonhypoxic Conditions: The Essential Role of Mitochondrial-derived Reactive Oxygen Species

2010 ◽  
Vol 21 (18) ◽  
pp. 3247-3257 ◽  
Author(s):  
David A. Patten ◽  
Véronique N. Lafleur ◽  
Geneviève A. Robitaille ◽  
Denise A. Chan ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Complex Iii ◽  
Oxygen Species ◽  
Ang Ii ◽  
Hypoxia Inducible Factor 1

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22phox siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1–dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase–generated ROS in Ang II–mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.

scholarly journals Angiotensin II evokes sensory long-term facilitation of the carotid body via NADPH oxidase

2011 ◽  
Vol 111 (4) ◽  
pp. 964-970 ◽  
Author(s):  
Ying-Jie Peng ◽  
Gayatri Raghuraman ◽  
Shakil A. Khan ◽  
Ganesh K. Kumar ◽  
Nanduri R. Prabhakar
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Carotid Body ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Ang Ii ◽  
Sensory Plasticity ◽  
Sensory Activity ◽  
Long Term Facilitation

We previously reported that reactive oxygen species generated by NADPH oxidase 2 (Nox2) induces sensory plasticity of the carotid body, manifested as a progressive increase in baseline sensory activity or sensory long-term facilitation (sLTF). ANG II, a peptide generated within the carotid body, is a potent activator of Nox2. In the present study, we tested the hypothesis that ANG II evokes sLTF of the carotid body via Nox2 activation. Experiments were performed on carotid bodies ex vivo from adult rats and mice. Sensory activity was recorded from the carotid sinus nerve. Repetitive (5 times for 30 s each at 5-min intervals), but not continuous (for 150 s), application of 60 pM ANG II evoked robust sLTF of the carotid body. ACh, ATP, substance P, and KCl, when applied repetitively, stimulated the carotid body but did not evoke sLTF. Reactive oxygen species levels increased in response to repetitive applications of ANG II, and this effect was blocked by apocynin, an inhibitor of Nox2, as well as losartan, an angiotensin type 1 (AT1) receptor antagonist. Losartan, apocynin, and 4-(2-aminoethyl)benzenesulfonyl fluoride prevented ANG II-induced sLTF, which was absent in mice deficient in gp91phox, the catalytic subunit of the Nox2 complex. These results demonstrate that repetitive application of ANG II induces sLTF of the carotid body via activation of Nox2 by AT1 receptors.

scholarly journals NADPH oxidase‐derived reactive oxygen species regulate Ang II‐induced contractions via p38/MK2 pathway in the mouse mesenteric artery

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Peter Martinka ◽  
Sebastian Schmidt ◽  
Michael Fähling ◽  
Andreas Steege ◽  
Matthias Gaestel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Mesenteric Artery ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Ang Ii

Angiotensin II Mediates High Glucose-Induced TGF-β1 and Fibronectin Upregulation in HPMC through Reactive Oxygen Species

2005 ◽  
Vol 25 (1) ◽  
pp. 38-47 ◽  
Author(s):  
Hyunjin Noh ◽  
Hunjoo Ha ◽  
Mi Ra Yu ◽  
Young Ok Kim ◽  
Ji Hye Kim ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Protein Expression ◽  
High Glucose ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Ang Ii ◽  
Fibronectin Expression ◽  
Tgf Β1

Objective To demonstrate the presence of an independent renin–angiotensin system (RAS) in the peritoneum and to determine the role of locally produced angiotensin (Ang) II in high glucose-induced upregulation of transforming growth factor (TGF)-β1 and fibronectin by human peritoneal mesothelial cells (HPMC). Methods In cultured HPMC, the expression of mRNAs for angiotensinogen, angiotensin-converting enzyme (ACE), Ang II type 1 receptor (AT1), and TGF-β1 was evaluated by real-time polymerase chain reaction; ACE, AT1, and fibronectin proteins by Western blot analysis; and Ang I, Ang II, and TGF-β1 proteins by ELISA. Dichlorofluorescein (DCF)-sensitive cellular reactive oxygen species (ROS) were measured by fluorometry. Results HPMC constitutively expressed all the components of RAS, and 50 mmol/L D-glucose (high glucose) significantly increased angiotensinogen, ACE, and AT1 mRNAs and ACE, AT1, and Ang II proteins. Ang II increased TGF-β1 and fibronectin protein expression and DCF-sensitive cellular ROS. Losartan prevented Ang II-induced increase in cellular ROS. Both losartan and captopril inhibited high glucose-induced upregulation of TGF-β1 and fibronectin expression in HPMC in a dose-dependent manner. Antioxidant catalase and NADPH oxidase inhibitor diphenyleneiodinium effectively inhibited Ang II-induced TGF-β1 and fibronectin protein expression. Conclusions The present data demonstrate that HPMC constitutively express RAS, that Ang II produced by HPMC mediates high glucose-induced upregulation of TGF-β1 and fibronectin expression, and that Ang II-induced TGF-β1 and fibronectin expression in HPMC is mediated by NADPH oxidase-dependent ROS. These data suggest that locally produced Ang II and ROS in the peritoneum may be potential therapeutic targets in peritoneal fibrosis during long-term peritoneal dialysis.

Cooperative interaction between reactive oxygen species and Ca2+ signals contributes to angiotensin II-induced hypertrophy in adult rat cardiomyocytes

2012 ◽  
Vol 302 (4) ◽  
pp. H901-H909 ◽  
Author(s):  
Rukhsana Gul ◽  
Asif Iqbal Shawl ◽  
Suhn-Hee Kim ◽  
Uh-Hyun Kim
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Adp Ribosyl Cyclase

Reactive oxygen species (ROS) and Ca2+ signals are closely associated with the pathogenesis of cardiac hypertrophy. However, the cause and effect of the two signals in cardiac hypertrophy remain to be clarified. We extend our recent report by investigating a potential interaction between ROS and Ca2+ signals utilizing in vitro and in vivo angiotensin II (ANG II)-induced cardiac hypertrophy models. ANG II-induced initial Ca2+ transients mediated by inositol trisphosphate (IP3) triggered initial ROS production in adult rat cardiomyocytes. The ROS generated by activation of the NAD(P)H oxidase complex via Rac1 in concert with Ca2+ activates ADP-ribosyl cyclase to generate cyclic ADP-ribose (cADPR). This messenger-mediated Ca2+ signal further augments ROS production, since 2,2′-dihydroxyazobenzene, an ADP-ribosyl cyclase inhibitor, or 8-Br-cADPR, an antagonistic analog of cADPR, abolished further ROS production. Data from short hairpin RNA (shRNA)-mediated knockdown of Akt1 and p47phox demonstrated that Akt1 is the upstream key molecule responsible for the initiation of Ca2+ signal that activates p47phox to generate ROS in cardiomyocytes. Nuclear translocation of nuclear factor of activated T-cell in cardiomyocytes was significantly suppressed by treatment with NAD(P)H oxidase inhibitors as well as by shRNA against Akt1 and p47phox. Our results suggest that in cardiomyocytes Ca2+ and ROS messengers generated by ANG II amplify the initial signals in a cooperative manner, thereby leading to cardiac hypertrophy.

scholarly journals Role of NADPH Oxidase-Mediated Reactive Oxygen Species in Podocyte Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Shan Chen ◽  
Xian-Fang Meng ◽  
Chun Zhang
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Epithelial To Mesenchymal Transition ◽  
Kidney Diseases ◽  
Treatment Strategies ◽  
Reactive Oxygen ◽  
Glomerular Sclerosis ◽  
Oxygen Species ◽  
Podocyte Injury ◽  
Mesenchymal Transition

Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and implications for potential treatment strategies in proteinuric kidney diseases (Zhang et al., 2012). Reactive oxygen species (ROS) are cellular signals which are closely associated with the development and progression of glomerular sclerosis. NADPH oxidase is a district enzymatic source of cellular ROS production and prominently expressed in podocytes (Zhang et al., 2010). In the last decade, it has become evident that NADPH oxidase-derived ROS overproduction is a key trigger of podocyte injury, such as renin-angiotensin-aldosterone system activation (Whaley-Connell et al., 2006), epithelial-to-mesenchymal transition (Zhang et al., 2011), and inflammatory priming (Abais et al., 2013). This review focuses on the mechanism of NADPH oxidase-mediated ROS in podocyte injury under different pathophysiological conditions. In addition, we also reviewed the therapeutic perspectives of NADPH oxidase in kidney diseases related to podocyte injury.

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