Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats

Mita, Shin-ichiro; Kobayashi, Noboru; Yoshida, Kenichi; Nakano, Shigefumi; Matsuoka, Hiroaki

doi:10.1097/00004872-200501000-00017

Cited by 61 publications

(50 citation statements)

References 31 publications

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“…This was indicated by induced phosphorylation of p38 MAPK and increased cardiac lipid peroxide and malondialdehyde levels. In line with the increased activity of RHOA, which has been reported to decrease levels of eNOS [13], eNOS levels were reduced in diabetic rat hearts. In contrast, atorvastatin treatment resulted in normalisation of diabetes-induced RAC1 and RHOA levels in parallel with reduced p38 MAPK phosphorylation and lipid peroxide levels and increased levels of eNOS.…”

Section: Effect Of Atorvastatin On Lipid Profilesupporting

confidence: 67%

“…Effect of atorvastatin treatment on eNOS protein production in the diabetic rat heart Since RHOA activity is known to be associated with decreased levels of eNOS [12,13], which partly due to its anti-inflammatory properties is an important marker of endothelial function, we investigated eNOS levels.…”

Section: Resultsmentioning

confidence: 99%

“…n=4 per group. Asterisks p<0.05 vs SD, section marks p<0.05 vs STZ + atorvastatin cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating the production of endothelial nitric oxide [45]; and (3) RHOA kinase inhibitors lead to increased eNOS levels and reduction of oxidative stress [13].…”

Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 99%

“…Cholesterol-independent or pleiotropic effects of statins include improved endothelial function, and reduction of oxidative stress and vascular inflammation. Many of these pleiotropic effects are mediated by antagonism of isoprenoid-mediated activation of small GTPbinding proteins, such as RHO family members, including ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) [11], activation of the latter being associated with decreased endothelial nitric oxide synthase (eNOS) expression and activity [12,13]. The cardioprotective effects of statins, independent of their hypolipidaemic effects, have already been demonstrated in normocholesterolaemic animal models of hypertrophy [14] and myocardial infarction [15].…”

Section: Introductionmentioning

confidence: 99%

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Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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Aims/hypothesis Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterollowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy. Methods Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-α, IL-1β, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/ macrophage antigen alpha, CD18/β2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferasep21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot. Results Diabetes was associated with induced cardiac stainings of TNF-α, IL-1β, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetesinduced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p<0.05) and 3.2-fold (p<0.0005), respectively, and normalised the reduced eNOS production caused by diabetes. Conclusions/interpretation These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

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Section: Effect Of Atorvastatin On Lipid Profilesupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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“…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%

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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Connective tissue growth factor: Context‐dependent functions and mechanisms of regulation

2009

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Connective tissue growth factor (CTGF, CCN2) is a secreted matricellular protein, the functions of which depend on the interactions with other molecules in the microcellular environment. As an example of context-dependent activity of CTGF, this review will outline different aspects of CTGF function in relation to angiogenesis. CTGF is barely expressed in normal adult tissue, but is strongly upregulated in fibrotic tissue and is also increased during development, in wound healing, or in certain types of cancer. Accordingly, gene expression of CTGF is tightly regulated. To highlight the complexity of the regulation of CTGF gene expression, we discuss here the mechanisms involved in CTGF regulation by TGFbeta in different cell types, and the mechanisms related to CTGF gene expression in cells exposed to mechanical forces. Finally, we will touch upon novel aspects of epigenetic regulation of CTGF gene expression. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

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Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats

Abstract: Inhibiting the Rho-kinase pathway may play a key role in the cardioprotective effect on cardiovascular remodeling associated with eNOS and the oxidative stress-LOX-1 pathway in DS rats, and may be at least a potential therapeutic strategy for hypertension with cardiac hypertrophy.

Cited by 61 publications

References 31 publications

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

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

Connective tissue growth factor: Context‐dependent functions and mechanisms of regulation

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