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Abstract: Tumor necrosis factor (TNF-α) is a pleiotropic cytokine exerting both inflammatory and cell death activity and is thought to play a role in the pathogenesis of atherosclerosis. The present study was designed to examine whether the raloxifene analogue, LY117018 could inhibit TNF-α-induced apoptosis in vascular endothelial cells and to clarify the involved mechanisms. Apoptosis of endothelial cells was determined by DNA fragmentation assay and the activation of caspase-3. LY117018 significantly inhibited TNF-α-induced caspase-3 activation and cell DNA fragmentation levels in bovine carotid artery endothelial cells. The inhibitory effect of LY117018 was abolished by an estrogen receptor antagonist ICI 182,780. p38 MAPK, JNK, ERK1/2 and Akt have been shown to act as apoptotic or anti-apoptotic signals. TNF-α stimulated the phosphorylation levels of p38 MAPK, JNK, ERK1/2 and Akt in vascular endothelial cells. TNF-α-induced apoptosis was significantly decreased by SB203580, a p38 MAPK inhibitor or SP600125, a JNK inhibitor, but was enhanced by an ERK1/2 pathway inhibitor, PD98059 or a PI3-kinase/Akt pathway inhibitor, wortmannin. The anti-apoptotic effect of LY117018 was abrogated only by PD98059 but was not affected by the inhibitors for p38 MAPK, JNK, or Akt. LY117018 stimulated the further increase in phosphorylation of ERK1/2 in TNF-α treated endothelial cells but it did not affect phosphorylation levels of p38 MAPK, JNK or Akt. These results suggest that LY 110718 prevents caspase-3 dependent apoptosis induced by TNF-α in vascular endothelial cells through activation of the estrogen receptors and the ERK1/2 signaling pathway. [Copyright &y& Elsevier]

Objectives: The aim of this study was to compare the effects of paclitaxel, sirolimus, and everolimus on the senescent phenotype in human endothelial cells, and to further investigate possible involvement of mammalian sirtuin 1 (Sirt1) down-regulation as a mechanism. Background: Endothelial cell senescence may play a role in impaired re-endothelialization after drug-eluting stent (DES) implantation. Recently, the down-regulation of Sirt1 has been shown to mediate oxidative stress-induced endothelial senescence. Methods: Senescent human umbilical vein endothelial cells (HUVEC) were judged by senescence-associated β-galactosidase assay (SA-βgal), morphological appearance, and plasminogen activator inhibitor (PAI)-1. Results: Treatment with paclitaxel, sirolimus, and everolimus significantly caused a senescent phenotype and PAI-1 up-regulation, associated with a decrease in endothelial nitric oxide synthase (eNOS) and Sirt1 expression. Overexpression of Sirt1 or Sirt1 activation reversed the sirolimus- or everolimus-induced senescent phenotype. Interestingly, paclitaxel-induced senescence was not suppressed by Sirt1 overexpression, suggesting the existence of a different mechanism. Cilostazol markedly inhibited the sirolimus- or everolimus-induced senescent phenotype (sirolimus or everolimus [2.5 nmol/l]; 49.2% or 53.0% SA-βgal positive vs. only 13.6% or 14.6% with cilostazol [100 μmol/l]) and PAI-1 up-regulation, but had no influence on the effects of paclitaxel. Finally, aspirin significantly blunted sirolimus- or everolimus-induced senescence, but neither ticlopidine nor clopidogrel had any effects. Conclusions: Sirolimus and everolimus induce endothelial senescence involving down-regulation of Sirt1. In contrast, the development of endothelial senescence by paclitaxel involves a Sirt1-independent pathway. Because sirolimus and everolimus are involved in Sirt1 modulation, cilostazol rescues HUVEC from sirolimus- or everolimus-induced senescence. These results may have therapeutic implications in the clinical sequelae after DES implantation. [Copyright &y& Elsevier]

Mechanical forces and the activation of the renin-angiotensin system (RAS) may alter the NO/O2•- balance, imparing endothelial nitric oxide (NO) availability. This study investigates the link between RAS and NO/O2•- balance in human aortic endothelial cells (HAEC) exposed to pulsatile stretch with and without ACE inhibitor quinaprilat or angiotensin II type 1 (AT1) receptor antagonist losartan. Pulsatile stretch increased Ang II levels and O2•- production, reducing NO release. RAS blockade with quinaprilat or losartan restored the balance between NO and O2•-. These results provide a molecular basis for understanding the vascular protective effects of ACE inhibition and AT1 receptor antagonism. [ABSTRACT FROM AUTHOR]

Abstract: Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells. [Copyright &y& Elsevier]

A letter to the editor is presented which is concerned with sleep apnea in patients with metabolic syndrome.