Improvement of age‐related endothelial dysfunction by simvastatin: effect on NO and COX pathways

Sotomayor, Marı́a Álvarez de; Pérez‐Guerrero, Concepción; Herrrera, Ma Dolores; Jiménez, Luís; Marín, Roberto; Marhuenda, E.; Andriantsitohaina, Ramaroson

doi:10.1038/sj.bjp.0706420

Cited by 56 publications

(42 citation statements)

References 28 publications

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“…Interestingly, they were mimicked by inhibition of RhoA, suggesting that the mevalonate/ GGPP/RhoA pathway underlies the observed effects of simvastatin on miR-155 expression (103). The increased expression of eNOS mediated by statins translates into improved endothelial function, as evidenced in animal models of age-related (27) and high-fat-diet-induced (119) endothelial dysfunction. In addition to augmenting eNOS expression on a transcriptional and post-transcriptional level, statins have been shown to enhance eNOS activity at a post-translational level as well.…”

Section: Effects Of Statins On Enosmentioning

confidence: 99%

“…Statin-mediated alterations in the activity of pro-oxidant enzymes could also partially explain the beneficial antithrombotic effects of statins, as evidenced by reduced release of thromboxane A2 from aged rat aortas, in a cyclooxygenase-2-mediated way (27). Release of 8-isoprostane through cyclooxygenase-2 is elevated in spontaneously hypertensive rats; this is abrogated after atorvastatin treatment, leading to an improvement of endothelial function and restoration of vascular redox state (111).…”

Section: Effects Of Statins On Other Enzymatic Systems and Pathways Imentioning

confidence: 99%

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

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

116

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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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Section: Effects Of Statins On Enosmentioning

confidence: 99%

Section: Effects Of Statins On Other Enzymatic Systems and Pathways Imentioning

confidence: 99%

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

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

116

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“…In aorta from aged rats, simvastatin inhibited the generation of COX-2-derived contracting prostanoids. 10 In addition, atorvastatin reduced COX-2 expression in a rabbit model of atherosclerosis. 11 However, the impact of statins on the role of COX-2-derived prostanoids in endothelial dysfunction of peripheral resistance vessels in hypertension is presently unknown.…”

mentioning

confidence: 99%

Atorvastatin Prevents Endothelial Dysfunction in Mesenteric Arteries From Spontaneously Hypertensive Rats

et al. 2009

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Abstract-We investigated the effect of atorvastatin on cyclooxygenase (COX) contribution to endothelial dysfunction in spontaneously hypertensive rat (SHR) mesenteric resistance arteries. Atorvastatin (10 mg/kg per day, oral gavage) or its vehicle was administered for 2 weeks to male SHR or Wistar-Kyoto rats. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In Wistar-Kyoto rats, relaxation to acetylcholine was inhibited by N G -nitro-Larginine methyl ester and unaffected by SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), or ascorbic acid. In SHRs, the response to acetylcholine was attenuated, less sensitive to N G -nitro-L-arginine methyl ester, unaffected by SC-560, and enhanced by DuP-697 or SQ-29548 (thromboxane-prostanoid receptor antagonist) to a similar extent. Endothelium-dependent relaxation was normalized by ascorbic acid or apocynin (NADPH oxidase inhibitor), which also restored the inhibition by N G -nitro-L-arginine methyl ester. In atorvastatin-treated SHRs, relaxation to acetylcholine was normalized, fully sensitive to N G -nitro-L-arginine methyl ester, and not affected by SC-560, DuP-697, SQ 29548, or antioxidants. Dihydroethidium assay showed an increased intravascular superoxide generation in SHRs, which was abrogated by atorvastatin. RT-PCR revealed a COX-2 induction in SHR arteries, which was downregulated by atorvastatin. The release of prostacyclin and 8-isoprostane was higher from SHR than Wistar-Kyoto mesenteric vessels. COX-2 inhibition and apocynin decreased 8-isoprostane without affecting prostacyclin levels. Atorvastatin increased phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS 1177 , and inducible NO synthase levels in SHR mesenteric vessels and decreased 8-isoprostane release. In conclusion, COX-2-derived 8-isoprostane contributes to endothelial dysfunction in SHR mesenteric arteries. Atorvastatin restores NO availability by increasing phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS 1177 , and inducible NO synthase levels and by abrogating vascular NADPH oxidase-driven superoxide production, which also results in a downregulation of COX-2-dependent 8-isoprostane generation. Key Words: cell signaling Ⅲ endothelium Ⅲ microcirculation Ⅲ oxidant stress Ⅲ NO G enetic hypertension is characterized by vascular endothelial dysfunction resulting mainly from increased generation of reactive oxygen species (ROS), which, in turn, cause NO breakdown. 1,2 It is accepted that such endothelial dysfunction is implicated in the pathogenesis of atherosclerosis, leading to an increased risk of cardiovascular events. 3 There is evidence indicating that cyclooxygenase (COX)-derived prostanoids are also involved in endothelial dysfunction. In particular, studies in spontaneously hypertensive rats (SHR) have shown that COX-2 can produce contracting prostanoids, which act on thromboxane-prostanoid (TP) receptors to maintain a pathological modulation of vascular responses. 4 -7 The ROS excess is hypothesized as 1 possible mech...

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“…노화로 염증성 세포들이 활성화되면 염증반응이 올라가 [11,13] 혈관이 막히 거나 좁아짐에 따라 고혈압, 뇌경색, 뇌출혈, 심근경색, 허혈 성 심장질환, 그리고 동맥류 같은 노인성혈관질환의 유병률 이 높아진다 [2]. 노인성혈관질환은 급증하고 있는 노인들의 사망원인으로 많은 차지를 하고 있으며 [3], 이에 따라 많은 연 구들이 수행되고 있지만 그 방어기전에 대한 연구는 비교적 적다.…”

Section: 서 론unclassified

Effects of L-Arginine Supplementation and Regular Exercise in D-Galactose Induced Aging Rat Aorta: Study on Inflammatory Factors, Vasodilation Regulatory Factors

Jin¹,

YiSub²,

Yoo³

et al. 2011

Journal of Life Science

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The purpose of this study was to identify the effects of an L-arginine supplementation and regular exercise training on NF-κB, TNF-α, iNOS, Cav-1, eNOS and Ang II in the aortas of D-galactose (D-gal) induced aging rats. The male Strague-Dawley rats were treated with a D-galactose aging inducing agent; the D-gal injection (50 mg/kg) was given intraperitoneally for 12 wk. Experimental groups were divided into five groups: (1) Young control group (Y-Con, n=8), (2) Aging control group (A-Con, n=8), (3) Aging exercise group (A-Ex, n=8), (4) Aging exercise group with L-arginine supplementation group (A-Ex+A , n=8), and (5) Aging with L-arginine supplementation group (A-A, n=8). The exercise consisted of running on a treadmill for 60 min/day at 20 m/min for 6 day/wk, at 0% gradient for 12 wk. The L-arginine supplementation was given orally at a dose of 150 mg/kg/day for 12 wk. The findings of this study were as follows: 1. NF-κB, TNF-α, iNOS, Cav-1 and Ang II proteins in the aortas of D-gal induced rats were significantly increased, however, L-arginine supplementation and regular exercise resulted in a significant inhibition in the expression of NF-κB, TNF-α, iNOS, Cav-1 and Ang II proteins. 2. eNOS protein in the aortas of D-gal induced rats was significantly decreased, however, L-arginine supplementation and regular exercise resulted in a significant increase in the expression of eNOS proteins. In conclusion, the findings of the present study reveal that L-arginine supplementation alone or regular exercise alone or in combination with L-arginine supplementation for 12 wk increases anti-inflammatory effects by decreasing NF-κB, TNF-α, and iNOS protein expressions within the aortic tissue. In addition, L-arginine supplementation alone or regular exercise alone or in combination with L-arginine supplementation may prevent endothelial function by up-regulation of eNOS protein in the aortas of D-gal induced aging rats.

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Improvement of age‐related endothelial dysfunction by simvastatin: effect on NO and COX pathways

Cited by 56 publications

References 28 publications

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

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

Atorvastatin Prevents Endothelial Dysfunction in Mesenteric Arteries From Spontaneously Hypertensive Rats

Effects of L-Arginine Supplementation and Regular Exercise in D-Galactose Induced Aging Rat Aorta: Study on Inflammatory Factors, Vasodilation Regulatory Factors

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