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1.
Simão S Gomes P Pinto V Silva E Amaral JS Igreja B Afonso J Serrão MP Pinho MJ Soares-da-Silva P 《Experimental gerontology》2011,46(6):468-474
Oxidative stress has been hypothesized to play a role in aging and age-related disorders, such as hypertension. This study compared levels of oxidative stress and renal expression of oxidant and antioxidant enzymes in male normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) at different ages (3 and 12 months). In the renal cortex of 3-month old SHR increases in hydrogen peroxide (H2O2) were accompanied by augmented expression of NADPH oxidase subunit Nox4 and decreased expression of antioxidant enzymes SOD1 and SOD3. A further increase in renal H2O2 production and urinary TBARS was observed in 12-month old WKY and SHR as compared with 3-month old rats. Similarly, expressions of NADPH oxidase subunit p22phox, SOD2 and SOD3 were markedly elevated with age in both strains. When compared with age-matched WKY, catalase expression was increased in 3-month old SHR, but unchanged in 12-month old SHR. Body weight increased with aging in both rat strains, but this increase was more pronounced in WKY. In conclusion, renal oxidative stress in 12-month old SHR is an exaggeration of the process already observed in the 3-month old SHR, whereas the occurrence of obesity in 12-month old normotensive rats may partially be responsible for the age-related increase in oxidative stress. 相似文献
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OBJECTIVE: We have previously shown an enhanced expression of Gialpha proteins in spontaneously hypertensive rats (SHR) that precedes the development of hypertension. Since oxidative stress has been shown to be increased in SHR, the present studies were undertaken to examine the role of oxidative stress in enhanced expression of Gialpha proteins in SHR. METHODS: Aortic vascular smooth muscle cells (VSMC) from 12-week-old SHR and Wistar-Kyoto (WKY) rats were used for the present studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gialpha-2 and Gialpha-3) and stimulatory proteins (Gsalpha) were determined by western blotting techniques. Adenylyl cyclase activity was determined by measuring [32P]cAMP formation from [alpha-32P]ATP. RESULTS: VSMC from SHR exhibited enhanced expression of Gialpha-2 and Gialpha-3 proteins as compared with age-matched WKY rats; however, the levels of Gsalpha proteins were not different between the two groups. The levels of superoxide anion (O2-) were also increased in SHR as compared with WKY rats, and losartan, an AT1 receptor antagonist, restored the enhanced levels to control WKY rat levels. Treatment of VSMC with antioxidants such as N-acetyl-L-cysteine (NAC) or diphenyleneiodonium (DPI) for 24 h decreased the enhanced expression of Gialpha-2 and Gialpha-3 proteins in a concentration-dependent manner in VSMC from SHR. In addition, the inhibition of forskolin-stimulated enzyme activity by low concentrations of GTPgammaS (receptor-independent Gi functions) and C-ANP4-23-mediated inhibition of adenylyl cyclase (receptor-dependent Gi functions) that were significantly enhanced in SHR were restored to WKY rat levels by NAC and DPI treatments. Similarly, diminished stimulation of adenylyl cyclase by GTPgammaS, isoproterenol and sodium fluoride in SHR was also restored towards control WKY rat levels by NAC and DPI treatments. Furthermore, PD98059, a selective inhibitor of mitogen-activated protein kinase, was able to restore the enhanced expression of Gialpha proteins in VSMC from SHR towards WKY rat levels. In addition, the enhanced activity of extracellular signal-regulated kinase 1/2 in SHR as compared with WKY rats, as demonstrated by enhanced phosphorylation of extracellular signal-regulated kinase 1/2, was also restored to WKY rat levels by NAC or DPI. CONCLUSIONS: These results suggest that enhanced levels of Gialpha proteins and associated functions in SHR may be attributed to the enhanced oxidative stress present in SHR, which exerts its effects through the mitogen-activated protein kinase signaling pathway. 相似文献
3.
Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: Enhancement by angiotensin II
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Patrick J. Pagano Justin K. Clark M. Eugenia Cifuentes-Pagano Stacie M. Clark Gayle M. Callis Mark T. Quinn 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(26):14483-14488
Superoxide anion (O2−) plays a key role in the endogenous suppression of endothelium-derived nitric oxide (NO) bioactivity and has been implicated in the development of hypertension. In previous studies, we found that O2− is produced predominantly in the adventitia of isolated rabbit aorta and acts as a barrier to NO. In the present studies, we characterize the enzyme responsible for O2− production in the adventitia and show that this enzyme is a constitutively active NADPH oxidase with similar composition as the phagocyte NADPH oxidase. Constitutive O2−-generating activity was localized to aortic adventitial fibroblasts and was enhanced by the potent vasoconstrictor angiotensin II. Immunohistochemistry of aortic sections demonstrated the presence of p22phox, gp91phox, p47phox, and p67phox localized exclusively in rabbit aortic adventitia, coincident with the site of staining for O2− production. Furthermore, immunodepletion of p67phox from adventitial fibroblast particulates resulted in the loss of NADPH oxidase activity, which could be restored by the addition of recombinant p67phox. Further study into the regulation of this adventitial source of O2− is important in elucidating the mechanisms regulating the bioactivity of NO and may contribute to our understanding of the pathogenesis of hypertension. 相似文献
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Huaqing Zhu Limei Shan Tianqing Peng 《Journal of molecular and cellular cardiology》2009,47(2):264-274
The purpose of this study was to investigate the role of Rac1 and estrogen in sex difference of cardiac tumor necrosis factor-alpha (TNF-α) expression during endotoxemia. Endotoxemia was induced in male and female mice by peritoneal injection of lipopolysaccharide (LPS, 4 mg/kg). Compared with female mice, male mice produced more TNF-α in the heart 4 h after LPS treatment, which were correlated with higher Rac1 and NADPH oxidase activity, more phosphorylation of ERK1/2 and p38 MAPK, and up-regulation of toll-like receptor-4 (TLR-4) expression in male mice. Cardiac specific Rac1 knockout or administration of 17β-estradiol down-regulated Rac1 expression, attenuated gp91phox-NADPH oxidase expression and activity, decreased phosphorylation of ERK1/2/p38 MAPK and inhibited cardiac TNF-α expression induced by LPS, suggesting an important role of Rac1 and estrogen in LPS-stimulated TNF-α expression in the heart. More importantly, the sex difference in TNF-α expression was abrogated by Rac1 knockout or gp91phox knockout and by administration of apocynin or N-acetylcysteine in LPS-stimulated mice. To investigate the functional significance of sex difference in endotoxemia, heart function was measured in isolated hearts with a Langendorff system. Male mice exhibited worse myocardial dysfunction compared with female in endotoxemia. Treatment of male mice with 17β-estradiol attenuated myocardial dysfunction during endotoxemia. In conclusion, LPS induces Rac1 activation, which contributes to NADPH oxidase activity and phosphorylation of ERK1/2/p38 MAPK, leading to TNF-α expression in the heart. The sex difference in TNF-α expression is estrogen-dependent and mediated via Rac1 dependent NADPH oxidase/ERK1/2 and p38 MAPK pathway in LPS-stimulated hearts. 相似文献
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Renal angiotensin II (AII) is suggested to play a role in the enhanced sodium reabsorption that causes a shift in pressure natriuresis in obesity related hypertension; however, the mechanism is not known. Therefore, to assess the influence of AII on tubular sodium transport, we determined the effect of AII on the Na+, K+-ATPase activity (NKA), an active transporter regulated by the AT1 receptor activity, in the isolated proximal tubules of lean and obese Zucker rats. Also, we determined the levels of the tubular AT1 receptor and associated signal transducing G proteins, as the initial signaling components that mediate the effects of AII on Na+, K+-ATPase activity. In the isolated proximal tubules, AII produced greater stimulation of the NKA activity in obese compared with lean rats. Determination of the AT1 receptors by Scatchard analysis of the [125I] Sar-Ang II binding and Western blot analysis in the basolateral (BLM) and brush border membrane (BBM) revealed a modest but significant increase (23%) in the AT1 receptor number mainly in the BLM of obese compared with lean rats. The AII affinity for AT1 receptors, as determined by IC50 values of AII to displace [125I] Sar-Ang II binding in BLM and BBM were similar in lean and obese rats. Western blot analysis revealed significant increases in Giα1, Giα2, Giα3, and Gq/11α in BLM and Giα1, Giα3, and Gq/11α in BBM of obese as compared with lean rats. The increase in the levels of the AT1 receptor and G proteins, mainly in the BLM, may be contributing to the enhanced AII-induced activation of NKA in the proximal tubules of obese rats. This phenomenon, in part, may be responsible for the increased sodium reabsorption and the development of hypertension in obese Zucker rats. 相似文献
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Konior A Klemenska E Brudek M Podolecka E Czarnowska E Beręsewicz A 《Journal of molecular and cellular cardiology》2011,50(4):686-694
Seasonality in endothelial dysfunction and oxidative stress was noted in humans and rats, suggesting it is a common phenomenon of a potential clinical relevance. We aimed at studying (i) seasonal variations in cardiac superoxide (O2−) production in rodents and in 8-isoprostane urinary excretion in humans, (ii) the mechanism of cardiac O2− overproduction occurring in late spring/summer months in rodents, (iii) whether this seasonal O2−-overproduction is associated with a pro-inflammatory endothelial activation, and (iv) how the summer-associated changes compare to those caused by diabetes, a classical cardiovascular risk factor.Langendorff-perfused guinea-pig and rat hearts generated ~ 100% more O2−, and human subjects excreted 65% more 8-isoprostane in the summer vs. other seasons. Inhibitors of NADPH oxidase, xanthine oxidase, and NO synthase inhibited the seasonal O2−-overproduction. In the summer vs. other seasons, cardiac NADPH oxidase and xanthine oxidase activity, and protein expression were increased, the endothelial NO synthase and superoxide dismutases were downregulated, and, in guinea-pig hearts, adhesion molecules upregulation and the endothelial glycocalyx destruction associated these changes. In guinea-pig hearts, the summer and a streptozotocin-induced diabetes mediated similar changes, yet, more severe endothelial activation associated the diabetes.These findings suggest that the seasonal oxidative stress is a common phenomenon, associated, at least in guinea-pigs, with the endothelial activation. Nonetheless, its biological meaning (regulatory vs. deleterious) remains unclear. Upregulated NADPH oxidase and xanthine oxidase and uncoupled NO synthase are the sources of the seasonal O2−-overproduction. 相似文献
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GDP-mannose pyrophosphorylase is a genetic determinant of ammonium sensitivity in Arabidopsis thaliana 总被引:1,自引:0,他引:1
Cheng Qin Weiqiang Qian Wenfeng Wang Yue Wu Chunmei Yu Xinhang Jiang Daowen Wang Ping Wu 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(47):18308-18313
Higher plant species differ widely in their growth responses to ammonium (NH4+). However, the molecular genetic mechanisms underlying NH4+ sensitivity in plants remain unknown. Here, we report that mutations in the Arabidopsis gene encoding GDP-mannose pyrophosphorylase (GMPase) essential for synthesizing GDP-mannose confer hypersensitivity to NH4+. The in planta activities of WT and mutant GMPases all were inhibited by NH4+, but the magnitude of the inhibition was significantly larger in the mutant. Despite the involvement of GDP-mannose in both l-ascorbic acid (AsA) and N-glycoprotein biosynthesis, defective protein glycosylation in the roots, rather than decreased AsA content, was linked to the hypersensitivity of GMPase mutants to NH4+. We conclude that NH4+ inhibits GMPase activity and that the level of GMPase activity regulates Arabidopsis sensitivity to NH4+. Further analysis showed that defective N-glycosylation of proteins, unfolded protein response, and cell death in the roots are likely important downstream molecular events involved in the growth inhibition of Arabidopsis by NH4+. 相似文献
10.
HIV protease inhibitors elicit volume-sensitive Cl current in cardiac myocytes via mitochondrial ROS
Wu Deng Jun Yin Clive M. Baumgarten 《Journal of molecular and cellular cardiology》2010,49(5):746-752
HIV protease inhibitors (HIV PI) reduce morbidity and mortality of HIV infection but cause multiple untoward effects. Because certain HIV PI evoke production of reactive oxygen species (ROS) and volume-sensitive Cl− current (ICl,swell) is activated by ROS, we tested whether HIV PI stimulate ICl,swell in ventricular myocytes. Ritonavir and lopinavir elicited outwardly rectifying Cl− currents under isosmotic conditions that were abolished by the selective ICl,swell-blocker DCPIB. In contrast, amprenavir, nelfinavir, and raltegravir, an integrase inhibitor, did not modulate ICl,swell acutely. Ritonavir also reduced action potential duration, but amprenavir did not. ICl,swell activation was attributed to ROS because ebselen, an H2O2 scavenger, suppressed ritonavir- and lopinavir-induced ICl,swell. Major ROS sources in cardiomyocytes are sarcolemmal NADPH oxidase and mitochondria. The specific NADPH oxidase inhibitor apocynin failed to block ritonavir- or lopinavir-induced currents, although it blocks ICl,swell elicited by osmotic swelling or stretch. In contrast, rotenone, a mitochondrial e− transport inhibitor, suppressed both ritonavir- and lopinavir-induced ICl,swell. ROS production was measured in HL-1 cardiomyocytes with C-H2DCFDA-AM and mitochondrial membrane potential (ΔΨm) with JC-1. Flow cytometry confirmed that ritonavir and lopinavir but not amprenavir, nelfinavir, or raltegravir augmented ROS production, and HIV PI-induced ROS production was suppressed by rotenone but not NADPH oxidase blockade. Moreover, ritonavir, but not amprenavir, depolarized ΔΨm. These data suggest ritonavir and lopinavir activated ICl,swell via mitochondrial ROS production that was independent of NADPH oxidase. ROS-dependent modulation of ICl,swell and other ion channels by HIV PI may contribute to some of their actions in heart and perhaps other tissues. 相似文献
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In this work, the synergistic inhibitions of tungstate (WO42−) and molybdate (MoO42−) anions, including role and mechanism, on the initiation of pitting corrosion (PC) for Q235 carbon steel in chloride (Cl−) solution were investigated with electrochemical and surface techniques. The pitting potential (Ep) of the Q235 carbon steel in WO42− + MoO42- + Cl− solution was more positive than that in WO42− + Cl− or MoO42− + Cl− solution; at each Ep, both peak potential and affected region of active pitting sites in WO42− + MoO42− + Cl− solution were smaller than those in WO42− + Cl− or MoO42− + Cl− solution. WO42− and MoO42− showed a synergistic role to inhibit the PC initiation of the Q235 carbon steel in Cl− solution, whose mechanism was mainly attributed to the influences of two anions on passive film. Besides iron oxides and iron hydroxides, the passive film of the Q235 carbon steel formed in WO42− + Cl−, MoO42− + Cl−, or WO42− + MoO42− + Cl− solution was also composed of FeWO4 plus Fe2(WO4)3, Fe2(MoO4)3, or Fe2(WO4)3 plus Fe2(MoO4)3, respectively. The film resistance and the defect quantity for Fe2(WO4)3 plus Fe2(MoO4)3 film were larger and smaller than those for FeWO4 plus Fe2(WO4)3 film and Fe2(MoO4)3 film, respectively; for the inhibition of PC initiation, Fe2(WO4)3 plus Fe2(MoO4)3 film provided better corrosion resistance to Q235 carbon steel than FeWO4 plus Fe2(WO4)3 film and Fe2(MoO4)3 film did. 相似文献
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Li Jing Lin Zhao Yi-Li Wang Feng-Ying Guo 《Clinical and experimental hypertension (New York, N.Y. : 1993)》2013,35(2):107-117
To further elucidate the molecular mechanisms involved in hypertensive vascular remodeling, an immunohistochemical technique and Western blot were applied to study phospho-extracellular signal-regulated kinase (ERK1/2) and transforming growth factor β1 (TGF-β1) expression in endothelial and vascular smooth muscle cell (VSMC) of the thoracic aorta and renal arterioles from SHR of different ages. Results of both the immunohistochemistry and Western blot assays showed that either the phospho-ERK1/2 at endothelium or VSMC of renal small arteries from SHR8, SHR16, and SHR20 groups and of the aorta from SHR16 and SHR20 were higher than that from control group. Comparing with that in the small arteries of the kidney, the phospho-ERK1/2 in the endothelium and in VSMC was markedly increased in the aorta, and high expression of TGF-β1 was detected in the aorta and kidney from SHR16 and SHR20 by Western blot. These results suggested that ERK 1/2 could be activated by phosphorylation with over-expression of TGF-β1 in the endothelium and in VSMC of aorta and renal arterioles from SHR, which might play an important role in VSMC proliferation under hypertension. 相似文献
13.
Magda Descorbeth 《Journal of molecular and cellular cardiology》2010,49(2):221-233
We have recently shown that high glucose increased the expression of Gq/11α, PLCβ and mediated signaling in A10 vascular smooth muscle cells (VSMC). Since high glucose has been shown to increase growth factor receptor activation, we investigated the role of epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) transactivation in high glucose-induced enhanced expression of Gq/11α and PLCβ. Pre-treatment of A10 VSMC with high glucose (26 mM) for 3 days, increased the levels of Gqα, G11α, PLCβ-1 and PLCβ-2 proteins which were restored to control levels by AG1478, an inhibitor of EGF-R, AG1295, an inhibitor of PDGF-R and PP2, an inhibitor of c-Src but not by PP3. In addition, endothelin-1 (ET-1)-stimulated production of IP3 that was enhanced by high glucose was also restored towards control levels by AG1478, AG1295 and PP2. High glucose also increased the phosphorylation of EGF-R and PDGF-R which was abolished by AG1478, AG1295 and PP2. Furthermore, high glucose-induced enhanced levels of Gqα, G11α and PLCβ were also attenuated by PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K). In addition, AG1478 and AG1295, also attenuated high glucose-induced enhanced phosphorylation of ERK1/2 and AKT. Furthermore, high glucose augmented the phosphorylation of c-Src which was attenuated by antioxidant, DPI. These results suggest that oxidative stress through the activation of c-Src and resultant transactivation of growth factor receptor contributes to the high glucose-induced enhanced expression of Gq/11α/PLC and -mediated cell signaling through MAPK/PI3K pathway. 相似文献
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Anand-Srivastava MB 《Current Cardiology Reviews》2010,6(4):298-308
Guanine nucleotide regulatory proteins (G-proteins) play a key role in the regulation of various signal transduction systems including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol turnover (PI). These are implicated in the modulation of a variety of physiological functions such as platelet functions, cardiovascular functions, including arterial tone and reactivity. Several abnormalities in adenylyl cyclase activity, cAMP levels and G proteins have shown to be responsible for the altered cardiac performance and vascular functions observed in cardiovascular disease states. The enhanced or unaltered levels of inhibitory G-proteins (Giα-2 and Giα-3) and mRNA have been reported in different models of hypertension, whereas Gsα levels were shown to be unaltered. These changes in G-protein expression were associated with Gi functions. The enhanced levels of Giα proteins precede the development of blood pressure and suggest that overexpression of Gi proteins may be one of the contributing factors for the pathogenesis of hypertension. The augmented levels of vasoactive peptides, including angiotensin II (AngII), were shown to contribute to enhanced expression of Giα proteins and associated adenylyl cyclase signaling and thereby increased blood pressure. In addition, enhanced oxidative stress in hypertension due to Ang II may also be responsible for the enhanced expression of Giα proteins observed in hypertension. The mechanism by which oxidative stress enhances the expression of Gi proteins appears to be through the activation of mitogen activated protein (MAP) kinase activity. 相似文献
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Increased myocardial NADPH oxidase activity in human heart failure 总被引:16,自引:0,他引:16
Heymes C Bendall JK Ratajczak P Cave AC Samuel JL Hasenfuss G Shah AM 《Journal of the American College of Cardiology》2003,41(12):2164-2171
OBJECTIVES: This study was designed to investigate whether nicotinamide adenine dinucleotide 3-phosphate (reduced form) (NADPH) oxidase is expressed in the human heart and whether it contributes to reactive oxygen species (ROS) production in heart failure. BACKGROUND: A phagocyte-type NADPH oxidase complex is a major source of ROS in the vasculature and is implicated in the pathophysiology of hypertension and atherosclerosis. An increase in myocardial oxidative stress due to excessive production of ROS may be involved in the pathophysiology of congestive heart failure. Recent studies have suggested an important role for myocardial NADPH oxidase in experimental models of cardiac disease. However, it is unknown whether NADPH oxidase is expressed in the human myocardium or if it has any role in human heart failure. METHODS: Myocardium of explanted nonfailing (n = 9) and end-stage failing (n = 13) hearts was studied for the expression of NADPH oxidase subunits and oxidase activity. RESULTS: The NADPH oxidase subunits p22(phox), gp91(phox), p67(phox), and p47(phox) were all expressed at messenger ribonucleic acid and protein level in cardiomyocytes of both nonfailing and failing hearts. NADPH oxidase activity was significantly increased in end-stage failing versus nonfailing myocardium (5.86 +/- 0.41 vs. 3.72 +/- 0.39 arbitrary units; p < 0.01). The overall level of oxidase subunit expression was unaltered in failing compared with nonfailing hearts. However, there was increased translocation of the regulatory subunit, p47(phox), to myocyte membranes in failing myocardium. CONCLUSIONS: This is the first report of the presence of NADPH oxidase in human myocardium. The increase in NADPH oxidase activity in the failing heart may be important in the pathophysiology of cardiac dysfunction by contributing to increased oxidative stress. 相似文献
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《American journal of hypertension》1996,9(8):833-837
We have recently shown an enhanced expression of Giα-2 and Giα-3 at protein and mRNA levels and their relationship with adenylyl cyclase regulation in hearts and aorta from spontaneously hypertensive rats (SHR). The present studies were undertaken to examine if the antihypertensive action of captopril, an angiotensin I converting enzyme (ACE) inhibitor, is associated with the interaction and modulation of G-proteins and adenylyl cyclase activity. SHR and age-matched WKY were divided into two groups. One group of rats received captopril (10 mg/kg body weight) intravenously, whereas the other group received only vehicle (0.9% saline). The levels of Giα-2 and Giα-3 proteins were determined by immunoblotting technique using specific antisera against these proteins. The levels of Giα-2 and Giα-3 proteins were significantly enhanced in hearts from SHR as compared to WKY and captopril treatment restored the enhanced levels of Giα-2 and Giα-3 observed in SHR by about 70% to 80% towards WKY control rats. However, captopril slightly decreased the levels of Giα2 and Giα3 protein in normotensive WKY. In addition, the diminished stimulation of adenylyl cyclase by isoproterenol, glucagon and N-ethyl carboxamide adenosine and enhanced inhibition by inhibitory hormones such as C-type natriuretic peptide and angiotensin II observed in SHR was restored significantly by captopril treatment. These results suggest that one of the mechanisms by which captopril lowers the blood pressure may be due to its ability to modulate the levels of G-proteins and adenylyl cyclase activity. 相似文献
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Chanhong Kim Keun Pyo Lee Aiswarya Baruah Mena Nater Cornelia G?bel Ivo Feussner Klaus Apel 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(24):9920-9924
Plastid development in seedlings of Arabidopsis thaliana is affected by the transfer of 1O2-mediated retrograde signals from the plastid to the nucleus and changes in nuclear gene expression during late embryogenesis. The potential impact of these mechanisms on plastid differentiation is maintained throughout seed dormancy and becomes effective only after seed germination. Inactivation of the 2 nuclear-encoded plastid proteins EXECUTER1 and EXECUTER2 blocks 1O2-mediated retrograde signaling before the onset of dormancy and impairs normal plastid formation in germinating seeds. This long-term effect of 1O2 retrograde signaling depends on the recruitment of abscisic acid (ABA) during seedling development. Unexpectedly, ABA acts as a positive regulator of plastid formation in etiolated and light-grown seedlings. 相似文献
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Murat Olukman Cahide Elif Orhan Fatma Gül Çelenk Sibel Ülker 《Journal of diabetes and its complications》2010,24(6):415-423
AimIncreased production of reactive oxygen species (ROS) in the diabetic vasculature results in the impairment of nitric oxide (NO)-mediated relaxations leading to impaired endothelium-dependent vasodilation. An important source of ROS is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the inhibition of this enzyme is an active area of interest. This study aimed to investigate the effects of apocynin, an NADPH oxidase inhibitor, on endothelial dysfunction and on the expression of NO synthase (NOS) and NADPH oxidase in thoracic aorta of diabetic rats.MethodStreptozotocin (STZ)-diabetic rats received apocynin (16 mg/kg per day) for 4 weeks. Endothelium-dependent and -independent relaxations were determined in thoracic aortic rings. Western blotting and RT-PCR analysis were performed for NOSs and NADPH oxidase in the aortic tissue.ResultsAcetylcholine-induced relaxations and l-NAME-induced contractions were decreased in diabetic aorta. The decrease in acetylcholine and l-NAME responses were prevented by apocynin treatment without a significant change in plasma glucose levels. Endothelial NOS (eNOS) protein and mRNA expression exhibited significant decrease in diabetes, while protein and/or mRNA expressions of inducible NOS (iNOS) as well as p22phox and gp91phox subunits of NADPH oxidase were increased, and these alterations were markedly prevented by apocynin treatment.ConclusionNADPH oxidase expression is increased in diabetic rat aorta. NADPH oxidase-mediated oxidative stress is accompanied by the decreased eNOS and increased iNOS expressions, contributing to endothelial dysfunction. Apocynin effectively prevents the increased NADPH oxidase expression in diabetic aorta and restores the alterations in NOS expression, blocking the vicious cycle leading to diabetes-associated endothelial dysfunction. 相似文献
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Anna Bogdanova Jeroen S. Goede Erwin Weiss Nikolay Bogdanov Poul Bennekou Ingolf Bernhardt Hans U. Lutz 《Haematologica》2010,95(2):189-198