Simvastatin Prevents Vascular Hyporeactivity During Inflammation

Pleiner, Johannes; Schaller, Georg; Mittermayer, Friedrich; Zorn, Stefan; Marsik, Claudia; Polterauer, S; Kapiotis, Stylianos; Wolzt, Michael

doi:10.1161/01.cir.0000147774.90396.ed

Cited by 103 publications

(81 citation statements)

References 52 publications

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“…Another study showed that 1-h exposure to TNF-α, IL-1β, or endotoxin impairs endothelial function in hand veins of healthy subjects (Bhagat et al 1996). Endothelial NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript dysfunction is also produced by intra-arterial endotoxin infusion, and this impairment can be prevented by pretreatment with a statin (Pleiner et al 2004). …”

Section: Human Studies Of Systemic Inflammation and Endothelial Dysfumentioning

confidence: 99%

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Huang

Vita

2006

Trends in Cardiovascular Medicine

118

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The importance of inflammation in the pathogenesis of atherosclerosis is well established. The vascular endothelium contributes to and is affected by the inflammatory process. For example, a variety of cytokines have the ability to "activate" the endothelium and thereby promote expression of adhesion molecules and chemotactic factors that accelerate the inflammatory process and direct accumulation of leukocytes to specific sites in the arterial tree. In experimental systems, activation of endothelial cells is also associated with a loss of the biologic activity of endothelium-derived nitric oxide, an effect that accelerates the inflammatory process and also promotes local thrombosis and impairs local control of vasomotor tone. Consistent with these experimental studies, recent studies have provided evidence that inflammation is associated with an impairment of nitric oxide-dependent responses in human subjects. This article will review the experimental and clinical studies that support the relevance of inflammation to nitric oxide bioactivity in human atherosclerosis.It is now well recognized that atherosclerosis is an inflammatory disease (Ross 1999). Systemic risk factors induce a state of inflammation that contributes to all stages of atherosclerosis from the initiating events in lesion formation to the latest phase when plaques rupture, thrombose, and produce clinical syndromes such as myocardial infarction or stroke (Libby et al. 2002). The importance of inflammation in atherosclerosis is supported by recent studies showing that elevated levels of inflammatory markers identify individuals with increased risk for cardiovascular events (Pearson et al. 2003). In particular, the acute phase reactant C-reactive protein (CRP) shows promise as a clinically useful marker of cardiovascular risk (Ridker 2003).The vascular endothelium is both affected by and contributes to the inflammatory process that leads to atherosclerosis. For example, proinflammatory factors "activate" endothelial cells to promote an atherogenic phenotype. The activated endothelium, in turn, expresses adhesion molecules and chemotactic factors that accelerate and localize the inflammatory process. An important consequence of endothelial activation is loss of the biologic activity of endotheliumderived nitric oxide. Investigators have argued that a broad alteration of endothelial function, including loss of nitric oxide under proinflammatory conditions, might be a critical mechanism that links systemic states of inflammation to atherosclerosis (Vallance et al. 1997). This article will review the recent studies that support the relevance of systemic inflammation to nitric oxide bioactivity in human subjects. The Endothelium as a Regulator of Vascular HomeostasisThe endothelium regulates vasomotor tone, blood fluidity, growth of vascular smooth muscle cells, and local inflammation by elaborating a number of paracrine factors, including nitric oxide (Widlansky et al. 2003a). Endothelium-derived nitric oxide is a potent vasodilator and acts ...

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Section: Human Studies Of Systemic Inflammation and Endothelial Dysfumentioning

confidence: 99%

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Huang

Vita

2006

Trends in Cardiovascular Medicine

118

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“…Human studies have demonstrated positive association between systemic inflammation induced by endotoxin infusion and marked endothelial dysfunction as well as impaired responses to vasoactive compounds (Pleiner et al, 2004). An analysis of the Framingham Heart Study Offspring cohort found that serum C-reactive protein, IL-6, and soluble intercellular adhesion molecule-1 levels inversely correlated with brachial artery flow-mediated dilation and reactive hyperemia in the forearm, although this relationship was weakened after adjusting for traditional risk factors (Vita et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Terutroban, a Thromboxane/Prostaglandin Endoperoxide Receptor Antagonist, Increases Survival in Stroke-Prone Rats by Preventing Systemic Inflammation and Endothelial Dysfunction: Comparison with Aspirin and Rosuvastatin

Ballerio¹,

Banfi

Nobili³

et al. 2010

J Pharmacol Exp Ther

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This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive strokeprone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Saltloaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B 2 levels, terutroban significantly increased survival (p Ͻ 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p Ͻ 0.001), and a delayed increase of proteinuria (p Ͻ 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1␤, transforming growth factor-␤, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis.Several clinical and experimental studies (Widlansky et al., 2003;Huang and Vita, 2006) support the hypothesis that endothelial dysfunction and systemic inflammation play key roles in the pathogenesis of vascular diseases, including myocardial and brain ischemia. Human studies have demonstrated positive association between systemic inflammation induced by endotoxin infusion and marked endothelial dysfunction as well as impaired responses to vasoactive compounds (Pleiner et al., 2004). An analysis of the Framingham Heart Study Offspring cohort found that serum C-reactive protein, IL-6, and soluble intercellular adhesion molecule-1 levels inversely correlated with brachial artery flow-mediated dilation and reactive hyperemia in the forearm, although this relationship was weakened after adjusting for traditional risk factors (Vita et al., 2004).Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and proteinuria and die after the onset Article, publication date, and citation information can be found at

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“…Besides their cholesterollowering effect, statins have anti-inflammatory and immunomodulatory benefits. They can inhibit lipopolysaccharide (LPS)-mediated activation of human peripheral mononuclear cells and endothelial cells (18) and reduce the level of the proinflammatory cytokines tumor necrosis factor ␣ (TNF-␣) and interleukin (IL)-6 (23), thereby suppressing vascular inflammation and stabilizing vulnerable plaques (17). However, little is known about the mechanisms responsible for these anti-inflammatory effects.…”

mentioning

confidence: 99%

Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells

Wang¹,

Zhang²,

Meng³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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In the present study, we tested our hypothesis that atorvastatin exerts its antiinflammation effect via suppressing LPS-induced rapid upregulation of Toll-like receptor 4 (TLR4) mRNA and its downstream p38, ERK, and NF-B signaling pathways in human umbilical-vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). TLR4 mRNA expression and its downstream kinase activities induced by LPS alone or atorvastatin ϩ LPS in endothelial cells were quantified using quantitative real-time PCR and enzyme-linked immunosorbent assay. Preincubation of LPS-stimulated endothelial cells with TLR4 siRNA was conducted to identify the target of the anti-inflammatory effects of atorvastatin. Atorvastatin incubation resulted in the reduction of LPS-induced TLR4 mRNA expression, ERK1/2 and P38 MAPK phosphorylation, and NF-B binding activity. Pretreatment with MEK/ERK1/2 inhibitor PD98059 attenuated atorvastatin ϩ LPSinduced NF-B activity but had no effect on P38 MAPK phosphorylation. In contrast, pretreatment with P38 MAPK inhibitor SB203580 resulted in upregulation of atorvastatin ϩ LPS-induced ERK1/2 phosphorylation but had no significant effects on NF-B activity. On the other hand, blocking NF-B with SN50 produced no effects on atorvastatin ϩ LPS-induced ERK1/2 and P38 MAPK phosphorylation. Moreover, TLR4 gene silencing produced the same effects as the atorvastatin treatment. In conclusion, atorvastatin downregulated TLR4 mRNA expression by two distinct signaling pathways. First, atorvastatin stabilized I-B␣, which directly inhibited NF-B activation. Second, atorvastatin inactivated ERK phosphorylation, which indirectly inhibited NF-B activation. Suppression of p38 MAPK by atorvastatin upregulates ERK but exerts no effect on NF-B.atherosclerosis; inflammation; NF-B TREATMENT WITH STATINS, competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA coenzyme A reductase, not only reduces the incidence of cardiovascular events (9) but also improves outcomes in patients with sepsis (1). Besides their cholesterollowering effect, statins have anti-inflammatory and immunomodulatory benefits. They can inhibit lipopolysaccharide (LPS)-mediated activation of human peripheral mononuclear cells and endothelial cells (18) and reduce the level of the proinflammatory cytokines tumor necrosis factor ␣ (TNF-␣) and interleukin (IL)-6 (23), thereby suppressing vascular inflammation and stabilizing vulnerable plaques (17). However, little is known about the mechanisms responsible for these anti-inflammatory effects.LPS is a unique glycolipid comprising most of the outer leaflet of the outer wall of Gram-negative bacteria, and LPS recognition and signal transmission are among the key events in the host defense reaction against Gram-negative bacteria. LPS may be linked to vascular disease, and low levels of circulating endotoxin in humans and rabbits have been shown to promote the development of atherosclerosis (11).Toll-like receptors (TLRs) are type-I transmembrane receptors expressed on the cell membrane after LPS stimulation. They are...

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Simvastatin Prevents Vascular Hyporeactivity During Inflammation

Cited by 103 publications

References 52 publications

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Terutroban, a Thromboxane/Prostaglandin Endoperoxide Receptor Antagonist, Increases Survival in Stroke-Prone Rats by Preventing Systemic Inflammation and Endothelial Dysfunction: Comparison with Aspirin and Rosuvastatin

Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells

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