Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-κB Induced by Oxidative Stress

Kobayashi, Noboru; Mita, Shin-ichiro; Yoshida, Kenichi; Honda, Takeshi; Kobayashi, Tsutomu; Hara, Kazuyoshi; Nakano, Shigefumi; Tsubokou, Yusuke; Matsuoka, Hiroaki

doi:10.1161/01.hyp.0000097547.35570.70

Cited by 82 publications

(76 citation statements)

References 38 publications

(40 reference statements)

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“…Celiprolol was also reported to activate eNOS through the PI3K-Akt signaling pathway. 18 Conversely, the impact on PIN may be a specific effect of ␤ 1 -blockers. It was reported that an association exists between nNOS decrease in the hypothalamus and enhanced sympathetic tone in rats with heart failure.…”

Section: Discussionmentioning

confidence: 99%

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Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

et al. 2004

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Background-The blockade of ␤-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective ␤ 1 -blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway. Methods and Results-In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N G -nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70Ϯ0.42 in TAC, 6.61Ϯ0.44 with celiprolol 100 mg · kg Ϫ1 · d Ϫ1 PO, PϽ0.01) and the ratio of lung weight to body weight (mg/g) (10.27Ϯ1.08 in TAC, 7.11Ϯ0.70 with celiprolol 100 mg · kg Ϫ1 · d Ϫ1 PO, PϽ0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice. Conclusions-These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective ␤ 1 -adrenergic receptor blockade and NO-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

“…sis. 16,18 Expression of these proteins was detected by use of the diaminobenzidine method and quantified by densitometry.…”

Section: No Measurementmentioning

confidence: 99%

Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

et al. 2004

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“…6,17 PCR was done using synthetic oligonucleotide primers as reported previously. 6,17 The numbers of PCR cycles for the 12 genes examined were as follows: eNOS, 30; iNOS, 31; NAD(P)H oxidase p22phox, 36; p47phox, 32; gp91phox, 33; LOX-1, 38; MR, 32; aldosterone synthase (CYP11B2), 31; sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA2), 32; transforming growth factor (TGF)-␤1, 32; type I collagen, 27; and GAPDH, 22.…”

Section: Quantification Of Mrna Using Rt-pcrmentioning

confidence: 99%

“…11,17 Activity of p65NF-B, PKC␤II, c-Src, p44/p42 Extracellular Signal-Regulated Kinase, p70 S6 Kinase, eNOS, and Akt p65NF-B, PKC␤II, c-Src, p44/p42 extracellular signal-regulated kinase (ERK), p70 S6 kinase (p70S6K), eNOS, and Akt phosphorylation was measured as described in detail previously. 6,14 …”

Section: Western Blot Analysismentioning

confidence: 99%

“…In addition, the production of reactive oxygen species (ROS) by NAD(P)H oxidase may be involved in vascular smooth muscle cell growth and the pathogenesis of hypertension, and we have shown recently that in deoxycorticosterone acetate-salt rats with left ventricular hypertrophy, NAD(P)H oxidase p22phox, p47phox, and gp91phox expression was upregulated in the left ventricle (LV), potentially contributing to endothelial dysfunction. 6 Moreover, recent reports have demonstrated that oxidized low-density lipoprotein receptor 1 (LOX-1) expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure. 7 Nuclear factor B (NF-B) activation is widely acknowledged to be required for the expression of a number of inflammatory and stress-response genes and those resulting in inducible NO synthase (iNOS) production.…”

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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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Gastroschisis: A gene–environment model involving the VEGF–NOS3 pathway

Lammer¹,

Iovannisci²,

Tom

et al. 2008

American J of Med Genetics Pt C

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Gastroschisis is a severe major malformation in which an infant is delivered with a portion of intestines and possible other abdominal organs extruding through a defect in the abdominal wall, usually to the right of the umbilical cord. Etiologies of gastroschisis are largely unknown, and even its pathogenesis is poorly understood. Several recent epidemiological studies have identified interactions between maternal smoking during pregnancy, genetic variants of endothelial nitric oxide synthase, and risk for gastroschisis. We present a brief review of the endothelial nitric oxide synthase pathway and its relationship to vasculogenesis, suggesting that disruption of this pathway by environmental exposures or by genetic variation may represent one pathogenetic model for gastroschisis.

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Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-κB Induced by Oxidative Stress

Cited by 82 publications

References 38 publications

Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

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

Gastroschisis: A gene–environment model involving the VEGF–NOS3 pathway

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