Suppression of Endothelial Nitric Oxide Production After Withdrawal of Statin Treatment Is Mediated by Negative Feedback Regulation of Rho GTPase Gene Transcription

Laufs, Ulrich; Endres, Matthias; Custodis, Florian; Gertz, Karen; Nickenig, Georg; Liao, James K.; Böhm, Michael

doi:10.1161/01.cir.102.25.3104

Cited by 239 publications

(201 citation statements)

References 31 publications

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“…20 Animal studies have demonstrated that the short-term withdrawal of statin therapy leads to a profound rebound phenomenon with impaired NO bioavailability. 21 Consistently, a recent study in patients with stable coronary heart disease showed a 3-fold increase in thrombotic vascular events after simvastatin treatment was stopped and continued with relatively lower doses of fluvastatin. 22 To test the hypothesis that the discontinuation of statin therapy has an adverse impact on patients with acute coronary syndromes, we performed the present subgroup analysis by using the data set of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial.…”

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confidence: 72%

Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes

et al. 2002

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.15). This was related to an increased event rate during the first week after onset of symptoms and was independent of cholesterol levels. In a multivariate model, troponin T elevation (Pϭ0.005), ST changes (Pϭ0.02), and continuation of statin therapy (Pϭ0.008) were the only independent predictors of patient outcome. Conclusions-Statin pretreatment in patients with acute coronary syndromes is associated with improved clinical outcome.However, discontinuation of statins after onset of symptoms completely abrogates this beneficial effect. (Circulation.

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confidence: 72%

Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes

et al. 2002

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“…2 Moreover, due to the association of cardiovascular risk factors and cardiovascular diseases with ED, prevalence of ED rises up to 50-75% in cardiovascular high-risk patients, depending on the method of evaluation used. 3,17,18 Patients suffering from the metabolic syndrome, including risk factors like hypertension, insulin resistance, obesity and dyslipidemia are considered to be predisposed to develop cardiovascular diseases, which contributes to the incremental role of the metabolic syndrome in health economics, especially in the industrialized Western countries. 19 The present study demonstrates a high prevalence of ED in hypertensive patients with the metabolic syndrome, who represent a cardiovascular high-risk population.…”

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confidence: 99%

Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome

2008

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Pathogenesis of erectile dysfunction (ED) is related to endothelial dysfunction and therefore associated with cardiovascular risk factors. Patients with a combination of risk factors, as in metabolic syndrome, are thus likely to have an increased risk of developing endothelial and ED. The angiotensin receptor antagonist irbesartan has been shown to improve endothelial function in cardiovascular high-risk patients, which suggests a beneficial effect of treatment with irbesartan on ED. The aim of the present study was to determine the influence of irbesartan on ED in patients with a metabolic syndrome. A total of 1069 consecutive hypertensive patients with a metabolic syndrome from the Documentation of hypertension and metabolic syndrome in patients with Irbesartan Treatment survey were included. Patients were treated with irbesartan or the combination of irbesartan/hydrochlorothiazide for 6 months. ED was assessed using the international index of erectile function. The Cologne Evaluation Questionnaire of Erectile Dysfunction served as a control. Erectile function increased significantly (Po0.0001) after 6 months of treatment with irbesartan, irrespective of dosage and independent of additional treatment with hydrochlorothiazide. Prevalence of ED declined to 63.7% from 78.5% at baseline, along with a significant increase in orgasmic function (Po0.001) and intercourse satisfaction (Po0.001). Treatment with irbesartan alone, as well as in combination with hydrochlorothiazide is associated with an improvement of sexual desire, frequency of sexual contacts and erectile function in hypertensive patients with the metabolic syndrome. These results suggest a beneficial role of angiotensin receptor antagonists in the treatment of metabolic syndrome, and ED.

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“…Because three-dimensional colocalization of intracellular proteins is regulated by cytoskeletal rearrangements, changes in statin-induced actin cytoskeleton could affect intracellular transport, membrane trafficking, mRNA stability and gene transcription. Indeed, statins have been reported to cause alterations in the actin cytoskeleton and the assembly of focal adhesion complexes by inhibiting RhoA and Rac1 isoprenylation [41].…”

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Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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Suppression of Endothelial Nitric Oxide Production After Withdrawal of Statin Treatment Is Mediated by Negative Feedback Regulation of Rho GTPase Gene Transcription

Abstract: Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.

Cited by 239 publications

References 31 publications

Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes

Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes

Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

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