Inhibition of Endothelial Nitric Oxide Synthase Activity by Protein Kinase C

Hirata, Ken–ichi; Kuroda, Ryo; Sakoda, Tsuyoshi; Katayama, Masaya; Inoue, N.; Suematsu, Masakuni; Kawashima, Seinosuke; Yokoyama, Mitsuhiro

doi:10.1161/01.hyp.25.2.180

Cited by 170 publications

(100 citation statements)

References 35 publications

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“…23 Moreover, there are some reports that eNOS is a PKC substrate, and PKC-mediated phosphorylation inhibits eNOS activity. 24 Thus, there is some possibility that NAD(P)H oxidase and PKC activity may suppress eNOS production.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

et al. 2006

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Abstract-Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor B (NF-B) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-B, protein kinase C␤II, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca 2ϩ -ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-B after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway. Key Words: aldosterone Ⅲ oxidative stress Ⅲ heart failure Ⅲ nitric oxide synthase Ⅲ signal transduction A ldosterone is implicated in the development of myocardial interstitial fibrosis and may play a critical role in the pathophysiology of heart failure, because there is evidence of an increased expression of the aldosterone synthase gene in the failing human heart, suggesting a role for locally produced aldosterone in the heart. 1 The pathophysiological role of aldosterone has received impressive support from 2 clinical studies, the Randomized ALdactone Evaluation Study (RALES) and the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS). 2,3 These studies showed that low doses of mineralocorticoid receptor (MR) antagonists led to a dramatic reduction of the mortality rate. However, little is known about the role of aldosterone in the development of cardiovascular remodeling and the progression to cardiac failure.The endothelium is an important modulator of vascular tone and function, in part by the synthesis and release of endothelial NO synthase (eNOS). Recently, some investigators 4,5 have sho...

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Section: Discussionmentioning

confidence: 99%

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

et al. 2006

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“…A fosforilação da eNOS pela PKC reduz sua atividade catalítica (76), que, por sua vez, seria acompanhada pela fosforilação da Thr495 e desfosforilação da Ser1177 (77). Tal interação entre PKC e eNOS sugere uma forte associação entre diabetes e redução da NOS renal.…”

Section: Lagranha Et Alunclassified

Bases moleculares da glomerulopatia diabética

Lagranha¹,

Fiorino²,

Casarini

et al. 2007

Arq Bras Endocrinol Metab

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RESUMOO principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-β1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-β1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes -e aditivos -na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional. ABSTRACT Molecular Bases of Diabetic Nephropathy.The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra-and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-β1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-β1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of d...

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“…There are some reports that endothelium nitric oxide synthase is a PKC substrate and PKC-mediated phosphorylation inhibits endothelium nitric oxide synthase activity. 20,21 Because nitric oxide is widely known to be a vasodilative agent, 22 decreased nitric oxide activity could attenuate the vascular tone, leading the decrease in CBF. Thus, there is a possibility that aldosterone induced vasoconstriction because of decreased endothelium nitric oxide synthase activity by PKC activation.…”

Section: Involvement Of Pkc In the Aldosterone-induced Coronary Vasocmentioning

confidence: 99%

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

et al. 2005

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Abstract-Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4Ϯ3.8 to 19.3Ϯ5.2 mL/100 g/min; PϽ0.05), along with decreases in fractional shortening (FS) (8.4Ϯ0.7 to 5.4Ϯ0.4%; PϽ0.05) and lactate extraction rate (LER) (Ϫ31.7Ϯ2.9 to Ϫ41.4Ϯ3.7%; PϽ0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKCdependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects. Key Words: aldosterone Ⅲ ischemia Ⅲ protein kinases A ldosterone modulates cardiovascular function in addition to the crucial role in sodium and potassium homeostasis through binding to the intracellular mineralocorticoid receptors (MRs). 1 These receptor-mediated effects with transcriptional modulation of target genes are termed genomic effects. 2 Recently, another pathway possibly mediated by the specific membrane receptors through which aldosterone acts, ie, nongenomic effects of aldosterone, has been investigated. [2][3][4] Although this nongenomic action of aldosterone was shown in a variety of tissues such as vascular smooth muscle cells or cardiomyocytes, the effects of aldosterone on vascular tone are divergent. 4 -9 Aldosterone increased systemic vascular resistance in humans, as shown in the first report on the nongenomic effects of aldosterone, whereas aldosterone inhibits vasoconstriction in renal afferent arterioles. 7-9 Until now, the rapid nongenomic effects of aldosterone on vascular tone of coronary artery and cardiac functions in vivo under ischemia are not still fully estimated. Moreover, several rapid aldosterone-induced changes of the concentration of intracellular second messengers have been described. 6,10,11 Aldosterone is reported to activate pro...

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Inhibition of Endothelial Nitric Oxide Synthase Activity by Protein Kinase C

Cited by 170 publications

References 35 publications

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

Bases moleculares da glomerulopatia diabética

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

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