Simvastatin Decreases Free Radicals Formation in the Human Abdominal Aortic Aneurysm Wall via NF-κB

Piechota-Polańczyk, Aleksandra; Gorąca, Anna; Demyanets, Svitlana; Mittlböck, Martina; Domenig, Christoph; Neumayer, Christoph; Wojta, Johann; Nanobachvili, Josif; Huk, Ihor; Klinger, Markus

doi:10.1016/j.ejvs.2012.04.020

Cited by 48 publications

(49 citation statements)

References 37 publications

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“…2 An increase in MMP9/TIMP2 complex after simvastatin may influence the process of AAA progression by inhibiting the degradation of elastic fibres, which may be another protective mechanism of simvastatin in patients with AAAs. 4,5 However, this needs to be further confirmed.…”

Section: Discussionmentioning

confidence: 74%

“…15,24 Recently, it was found that monocytes, the numbers of which are increased during aneurysm formation, act on endothelium leading to elevation of Similarly, in a previous study, it was shown that simvastatin decreased pro-inflammatory nuclear factor-kB (NF-kB) and extracellular regulated kinase (ERK) signalling pathways activity in aneurysmal wall. 4,5 It was documented that activation of ERK and NF-kB signalling pathways is associated with increased activity of MMP2 and MMP9 in vascular smooth muscle cells and in aneurysmal tissue during AAA progression. 26,27 The increased activity of pro-inflammatory signalling pathways and protease activity in aneurysmal wall may, in turn, influence thrombus formation.…”

Section: Discussionmentioning

confidence: 99%

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The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue

Piechota-Polańczyk

Demyanets

Mittlböck

et al. 2015

European Journal of Vascular and Endovascular Surgery

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue

Piechota-Polańczyk

Demyanets

Mittlböck

et al. 2015

European Journal of Vascular and Endovascular Surgery

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“…In animal models of hypertension and diabetes, statins elevate aortic catalase expression through a sirtuin-1-dependent pathway (80,116). A statin-induced increase in catalase levels has also been demonstrated in human abdominal aortic aneurysms (87).…”

Section: Fig 6 Effects Of Statins On Vascular Rac1 Activation Inmentioning

confidence: 99%

“…In a small, nonrandomized study, 3 months of pravastatin treatment (40 mg/day) before scheduled carotid endarterectomy led to a more stabilized phenotype of the carotid plaque, as evidenced by reduced lipid and inflammatory content, characterized by reduced activation of NF-jB (26). In the human abdominal aortic aneurysm wall, simvastatin suppresses ROS generation and NFjB activity (87). In a randomized trial, atorvastatin treatment (80 mg/day) 1 month before endarterectomy was associated with reduced NF-jB activation in circulating mononuclear cells and the carotid plaque, coupled with reduced inflammatory gene expression and cell infiltration of the plaque (78).…”

Section: Fig 7 Effects Of Statins On Nadph Oxidase In Ec Statins Smentioning

confidence: 99%

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

117

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Significance: Endothelial dysfunction and the imbalance between nitric oxide (NO) and reactive oxygen species production in the vascular endothelium are important early steps in atherogenesis, a major socioeconomic health problem. Statins have well-established roles in primary and secondary prevention of cardiovascular disease (CVD), due to both their lipid-lowering capacity and their pleiotropic properties. It is therefore important to understand the mechanisms by which statins can modify endothelial function and affect atherogenesis. Recent Advances: In the last decade, the concept of statin pleiotropy has been reinforced by a large number of cell culture, animal, and translational studies. Statins have been shown to suppress the activity of pro-oxidant enzymes (such as NADPH oxidase) and pro-inflammatory transcriptional pathways in the endothelium. At the same time, they enhance endothelial NO synthase expression and activity while they also improve its enzymatic coupling. This leads to increased NO bioavailability and improved endothelial function. Critical Issues: Despite significant recent advances, the exact mechanisms of statin pleitropy are still only partially understood. The vast majority of the published literature relies on animal studies, while the actual mechanistic studies in humans are limited. Future Directions: The success of statins as endothelium redox-modifying agents with a direct impact on clinical outcome highlights the importance of the endothelium as a therapeutic target in CVD. Better understanding of the mechanisms that underlie endothelial dysfunction could lead to the design of novel therapeutic strategies that target the vascular endothelium for the prevention and treatment of CVD. Antioxid. Redox Signal. 20, 1198Signal. 20, -1215

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“…Evidence of these roles can be found in the increased plasma levels of TNF-α in diabetic patients, which have been shown to impair the function of endothelial cells, as well as to enhance their aging and apoptosis (19)(20)(21). A previous in vitro study has shown that incubation of EPCs with TNF-α increases p38-phosphorylation, resulting in a reduction of total EPCs (22 (24)(25)(26)(27). Silent information regulator type-1 (SIRT1) is a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent class III histone deacetylases (HDACs).…”

Section: Introductionmentioning

confidence: 99%

Simvastatin attenuates TNF-α-induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1

Song

Zhang

et al. 2014

International Journal of Molecular Medicine

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Abstract. Endothelial progenitor cells (EPCs) originate from the bone marrow and can be classified as either early or late EPCs. The focus of this study was on late EPCs, as they play an important role in angiogenesis and vascular proliferation. Evidence suggests that inflammatory and oxidative changes can increase EPC apoptosis. Of note, tumor necrosis factor-α (TNF-α) is a contributing risk factor to the development of atherosclerosis and plays a key role as both an inflammatory mediator and an inducer of apoptosis in endothelial cells. Additionally, a member of the sirtuin family, silent information regulator type-1 (SIRT1), promotes cell survival by repressing p53-and non-p53-dependent apoptosis in response to DNA damage and oxidative stress. Statins have also been shown to play a key role in the prevention of endothelial apoptosis and senescence via their lipid-lowering and anti-inflammatory actions. However, there is little evidence that statins themselves attenuate EPC apoptosis induced by TNF-α. The aim of this study was to demonstrate the effectiveness of one of the most commonly used statins, simvastatin, on decreasing TNF-α-induced apoptosis in EPCs. The results indicated that SIRT1 protein expression was decreased by TNF-α in a time-and dose-dependent manner and that while TNF-α caused a marked increase in the percentage of apoptotic EPCs, application of simvastatin decreased this percentage. A high concentration of simvastatin promoted the expression of SIRT1 and increased the proliferation of EPCs. In conclusion, findings of this study showed that simvastatin is crucial in counteracting the TNF-α-induced apoptosis of EPCs and that this protection may involve the actions of SIRT1.

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Simvastatin Decreases Free Radicals Formation in the Human Abdominal Aortic Aneurysm Wall via NF-κB

Abstract: Our work demonstrates that simvastatin exerts profound effects on free radical formation in aortic aneurysms. We propose nuclear factor-kappaB (NF-kB) being involved in the signalling events. To the best of our knowledge, our report shows the first human data in this special field.

Cited by 48 publications

References 37 publications

The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue

The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Simvastatin attenuates TNF-α-induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1

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