Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase

Waßmann, Sven; Laufs, Ulrich; Bäumer, Anselm T.; Müller, Kirsten; Konkol, Christian; Sauer, Heinrich; Böhm, Michael; Nickenig, Georg

doi:10.1124/mol.59.3.646

Cited by 327 publications

(254 citation statements)

References 38 publications

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“…Effect of atorvastatin treatment on RHOA-and RAC1-GTPase activity in the diabetic rat heart To investigate the cholesterol-independent effects of atorvastatin, we analysed the activation of the small GTP-binding proteins, RAC1 and RHOA [11], which have both been suggested to be mediators of inflammation [23]. RAC1 and RHOAGTPase activity was 1.7-fold (p<0.05) and 1.6-fold (p<0.05) upregulated in diabetic compared with non-diabetic control LVs, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Effect of atorvastatin on intramyocardial inflammation Many of the pleiotropic effects of statins are mediated by antagonism of isoprenoid-mediated activation of small GTP-binding proteins, including RAC1 and RHOA [11], which have previously been suggested to be mediators of inflammation [23,40]. Both RAC1 [41] and RHOA GTPase [42] are involved in the regulation of the cytoskeleton network, which includes integrin-dependent leucocyte adhesion.…”

Section: Effect Of Atorvastatin On Lipid Profilementioning

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: Resultsmentioning

confidence: 99%

Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 99%

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

et al. 2007

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“…44 Statins downregulate AT1R expression in platelets and vascular smooth muscle cells. 45,46 Thus, simvastatin may prevent SAD-induced aggravation of hypertensive cardiac hypertrophy, at least in part, by inhibiting the angiotensin II-mediated mechanism. This issue should be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

et al. 2010

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Pronounced variability in blood pressure (BP) is an aggravating factor of hypertensive end-organ damage. However, its pathogenesis remains unknown. Statins have various protective effects on the cardiovascular system. Thus, we determined whether simvastatin would attenuate the aggravation of hypertensive cardiac remodeling in a rat model of hypertension with large BP variability, and also investigated the signaling mechanism involved in its effect. A model of hypertension with large BP variability was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). A SAD or sham operation was performed in 12-week-old rats. Thereafter, simvastatin (0.2 mg kg À1 per day) or vehicle was intraperitoneally administered every day. After 6 weeks , telemetric recordings revealed that SAD enhanced BP variability without changing the mean BP. SAD increased myocyte hypertrophy, myocardial fibrosis and macrophage infiltration associated with the upregulation of brain natriuretic peptide (BNP), type I procollagen, transforming growth factor (TGF)-b and monocyte chemoattractant protein (MCP)-1, and activation of RhoA, Ras and ERK1/2. Simvastatin did not change the mean BP or BP variability in SAD-operated SHRs. In SAD-operated SHRs, simvastatin attenuated myocyte hypertrophy and BNP expression, as well as RhoA, Ras and ERK1/2 activities. In contrast, simvastatin did not change myocardial fibrosis, macrophage infiltration, or the expression of procollagen and TGF-b or MCP-1 in SAD-operated SHRs. Simvastatin did not affect serum lipid levels. In conclusion, simvastatin attenuated the large BP variability-induced aggravation of cardiac hypertrophy, but not myocardial fibrosis, in SHRs. The activation of RhoA/Ras-ERK pathways may contribute to the aggravation of cardiac hypertrophy by a combination of hypertension and large BP variability.

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“…Indeed, Rac activity is closely related to ROS production and ROS generated by NADPH oxidase in response to growth factors and inflammatory cytokines is mediated by Rac [56]. Importantly, statins inhibit Rac1-mediated NADPH oxidase activity and thereby reduce angiotensin II-induced ROS production and hypertrophy in smooth muscle and heart [57,58]. The activation of Rac1 in the vascular wall has been associated with atherosclerosis, neointimal proliferation, cardiac hypertrophy and endothelial dysfunction [59].…”

Section: Statins and Racmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

532

394

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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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Inhibition of Geranylgeranylation Reduces Angiotensin II-Mediated Free Radical Production in Vascular Smooth Muscle Cells: Involvement of Angiotensin AT1 Receptor Expression and Rac1 GTPase

Cited by 327 publications

References 38 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

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

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