Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients

Perticone, Francesco; Ceravolo, Roberto; Maio, Raffaele; Cloro, C; Candigliota, Mafalda; Scozzafava, Angela; Mongiardo, Annalisa; Mattioli, Pier Luigi; Mastroroberto, Pasquale; Chello, Massimo

doi:10.1016/s0021-9150(00)00370-1

Cited by 68 publications

(37 citation statements)

References 40 publications

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“…29 Hypercholesterolemia is known to cause a reduction in both endothelium-dependent 29,[32][33][34] and endothelium-independent NO responses. 14 Although endothelium-independent effects are not as widely reported, this may be due primarily to the maximum dose of SNP used in previous studies, which is much lower than the highest dose we used in our study, as well as the much smaller sample size in those studies favoring a negative result.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia

et al. 2011

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Background-Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen-activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38␣/␤ MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia. Methods and Results-Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol Ͼ4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (nϭ27) or placebo (nϭ29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N G -monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (Pϭ0.01 and Pϭ0.03) compared with responses in control subjects (nϭ12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; Pϭ0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; Pϭ0.02), and to L-NMMA by 10% (95% confidence interval, Ϫ1 to 23; Pϭ0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, Ϫ81 to Ϫ6%; PϽ0.05) in patients treated with losmapimod compared with placebo. Conclusions-Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease. Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT00474864. (Circulation. 2011;123:515-523.) Key Words: endothelial function Ⅲ hypercholesterolemia Ⅲ nitric oxide Ⅲ p38 MAPK Ⅲ vasodilation A therosclerosis is regarded as a complex condition in which inflammation plays a pivotal role, involving low-density lipoprotein (LDL) deposition and oxidation, recruitment of inflammatory cells, and release of cytokines and endothelial dysfunction. 1,2 Reduced nitric oxide (NO) bioavailability accompanies all stages of atherosclerosis and is associated with increased cardiovascular risk. 3 Clinical Perspective on p 523The release of NO is a complex process that can be affected by a number of physiological and pathophysiological factors, 4 including serum levels of LDL, which, when oxidized, have increased atherogenic potential. 5 Oxidized LDL reduces NO bioavailability, destabilizes endothelial NO synthase mRNA, 6 Received February 26, 2010; accepted November 19, 2010 Several p38 MAPK inhibitors are effective in a variety o...

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Section: Discussionmentioning

confidence: 99%

Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia

et al. 2011

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“…The cholesterol-lowering effects are associated with improvements in endothelium-dependent vasodilation. 6,7 Cellular and animal investigations have demonstrated nonlipid benefits of statins that include upregulation of eNOS, reduction of oxidative stress, and antagonism of isoprenoidmediated activation of small GTP-binding proteins. 8 Corroborating these experimental studies, statin-mediated improvements in endothelial function have been demonstrated within days in humans, even after a single dose and before any significant lipid affect.…”

mentioning

confidence: 99%

Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein

Beckman

Liao

Hurley

et al. 2004

Circulation Research

116

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Abstract-Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins) may favorably affect endothelial function via nonlipid mechanisms. We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers. Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks, washed out for 4 weeks, and then crossed-over to the other treatment. Baseline low-density lipoprotein (LDL) levels were similar in smokers and healthy subjects, 103Ϯ22 versus 95Ϯ27 mg/dL, respectively (PϭNS) and were reduced similarly in smokers and control subjects by atorvastatin, to 55Ϯ30 and 58Ϯ20 mg/dL, respectively (PϭNS). Vascular ultrasonography was used to determine brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin-mediated, endothelium-independent vasodilation. To elucidate potential molecular mechanisms that may account for changes in endothelial function, skin biopsy specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine. Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment, 8.0Ϯ0.6% versus 12.1Ϯ1.1%, (Pϭ0.003). Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5Ϯ1.3% (Pϭ0.017 versus placebo) but did not change endothelium-dependent vasodilation in control subjects (to 11.0Ϯ0.8%, PϭNS). Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin. Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared with controls but unaffected by atorvastatin treatment. Atorvastatin restores endothelium-dependent vasodilation in normocholesterolemic cigarette smokers independent of changes in lipids. These results are consistent with a lipid-independent vascular benefit of statins but could not be explained by changes in eNOS message and tissue oxidative stress. These findings implicate a potential role for statin therapy to restore endothelial function and thereby investigate vascular disease in cigarette smokers. Key Words: cigarette smoking Ⅲ endothelial nitric oxide synthase Ⅲ hydroxymethylglutaryl CoA reductase inhibitor Ⅲ endothelial function Ⅲ oxidative stress C igarette smoking is a reversible risk factor for atherosclerosis. Smoking impairs endothelial function and creates a vascular environment that contributes to the development of atherosclerosis. 1,2 Putative mechanisms through which cigarette smoking alters endothelial function and particularly the bioavailability of nitric oxide (NO) in humans include increased oxidative stress, 3 alterations in endothelial nitric oxide synthase (eNOS), 4 and activation of rho kinase...

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“…[21][22][23] Statins have been shown to upregulate endothelial NO synthase (eNOS) expression and activity independent of LDL levels, 24 -28 potentially augmenting the availability of NO. Therefore, we hypothesize a beneficial effect of intensive lipid-lowering therapy by atorvastatin on NO-dependent vasoreactivity in patients with type 2 diabetes and mild dyslipidemia.…”

mentioning

confidence: 99%

Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes

Etten

Koning

Honing

et al. 2002

ATVB

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Abstract-Cardiovascular disease is the most important cause of morbidity and mortality in patients with type 2 diabetes.Endothelial dysfunction predicts cardiovascular outcome. Type 2 diabetes is characterized by endothelial dysfunction, which may be caused by dyslipidemia. Statin therapy restores endothelial function in hyperlipidemic patients. Therefore, we hypothesize a beneficial effect of atorvastatin on NO-dependent vasodilation in patients with type 2 diabetes and mild dyslipidemia (low density lipoproteins Ͼ4.0 mmol/L and/or triglycerides Ͼ1.8 mmol/L). We evaluated the effect of intensive lipid lowering (4 weeks of 80 mg atorvastatin once daily) on vasoreactivity in 23 patients with type 2 diabetes by using venous occlusion plethysmography. Twenty-one control subjects were matched for age, sex, body mass index, blood pressure, and smoking habits. Key Words: plethysmography Ⅲ nitric oxide Ⅲ type 2 diabetes Ⅲ dyslipidemia Ⅲ atorvastatin T ype 2 diabetes is associated with high morbidity and mortality caused by the early development of atherosclerosis. 1-3 Dyslipidemia is a characteristic feature of patients with type 2 diabetes and has been implicated in the pathogenesis of cardiovascular complications in these patients. 4 -7 Lipid-lowering therapy has been shown to be of major importance in reducing cardiovascular risk in diabetic patient groups. 8,9 The endothelium has emerged as a first-line defense mechanism against atherosclerosis. It has been shown that endothelial dysfunction predicts outcome in cardiovascularly compromised patient groups. 10 -12 In type 2 diabetes, endothelial dysfunction is characterized by an impaired availability of NO, 13-16 which may be caused by dyslipidemia. [17][18][19][20] In addition, impaired endothelium-independent vasoreactivity has also been shown, 14,15 suggesting impaired smooth muscle responsiveness to NO.3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibition is an effective lipid-lowering therapy that restores endothelial dysfunction in patients with hyperlipidemia. [21][22][23] Statins have been shown to upregulate endothelial NO synthase (eNOS) expression and activity independent of LDL levels, 24 -28 potentially augmenting the availability of NO. Therefore, we hypothesize a beneficial effect of intensive lipid-lowering therapy by atorvastatin on NO-dependent vasoreactivity in patients with type 2 diabetes and mild dyslipidemia. Methods Study DesignPatients with type 2 diabetes were treated with atorvastatin (80 mg once daily) for 4 weeks. Vasoreactivity was assessed 3 times in this group (at the initiation [week 0], after 4 weeks of atorvastatin treatment [week 4], and after stopping atorvastatin for 4 weeks) to demonstrate a potential reversibility of changes in vasoreactivity induced by statin therapy (week 8); this is considered an A-B-A scheme. Using this open-label prospective A-B-A design, a patient serves as his own control.

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Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients

Cited by 68 publications

References 40 publications

Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia

Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia

Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein

Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes

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