Endothelium-dependent vasodilatation varies during the menstrual cycle. The endogenous estradiol may be involved in this menstrual cycle-related vasodilatation.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

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Abstract-Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K-dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 mol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which was increased by Pi in a concentration-dependent manner, and not by inhibiting sodium-dependent phosphate cotransporter (NPC) activity, another mechanism regulating HASMC calcification. Furthermore, the antiapoptotic effect of statins was dependent on restoration of Gas6, whose expression was downregulated by Pi. Restoration of Gas6 mRNA by statins was mediated by mRNA stabilization, and not by an increase in transcriptional activity. Suppression of Gas6 using small interfering RNA and the Axl-extracellular domain abolished the preventive effect of statins on Pi-induced apoptosis and calcification. These data demonstrate that statins protected HASMC from Pi-induced calcification by inhibiting apoptosis via restoration of the Gas6-Axl pathway. Key Words: calcification Ⅲ statins Ⅲ apoptosis Ⅲ Gas6 Ⅲ Axl V ascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology, because this lesion is associated with cardiovascular disease. 1,2 It has been recognized that statins exhibit various protective effects against atherosclerosis, including modification of endothelial function, 3 decreased inflammation, 4 and inhibition of vascular smooth muscle cell (VSMC) proliferation and migration, 5 all of which cannot be accounted for by lipid reduction. One of the interesting pleiotropic effects of statins is the inhibition of vascular calcification. Results from clinical trials suggest an association of statin use with slowed progression of calcific aortic stenosis 6 -8 and coronary artery calcification. 9 Statins also inhibited calcification of atherosclerotic plaques in experimental hyperlipidemic animals. 10,11 On the other hand, some recent clinical trials were not able to find such an inhibitory effect. 12,13 To clarify these discrepancies, it is important to identify the detailed regulatory mechanism of vascular calcification and the target of effect of statins.Based on clinical findings, 14 inorganic phosphate (Pi) has been shown to be an important inducer of VSM...

BACKGROUND: Obesity has been reported to be associated with coronary artery disease and other atherosclerotic diseases. Recently, evidence has accumulated indicating that intra-abdominal visceral fat accumulation contributes to atherogenesis; however, the mechanism underlying this remains to be determined. This study was undertaken to elucidate whether intra-abdominal visceral fat accumulation impairs vascular endothelial function in obese men. METHODS AND RESULTS: Thirty-eight obese men (body mass index (BMI) ! 26.0), aged 19±64 y (mean age 37.6 AE 1.8 y) and 23 age-matched non-obese subjects were examined. According to the ratio of the maximum thickness of preperitoneal fat to the minimum thickness of subcutaneous fat (Pmax/Smin) obtained by longitudinal ultrasound scanning in the subxiphoid region in obese men, we divided obese subjects into two categories; visceral (PmaxaSmin ! 1; n 23) and subcutaneous type (PmaxaSmin`1; n 15). To investigate endothelial function, we performed ultrasound measurement of the brachial artery diameter non-invasively both at rest and during reactive hyperaemia in the muscle distal to the brachial artery which causes endothelium-dependent vasodilatation. The brachial diameter change was also measured after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. Flow-mediated diameter (D) increase (%FMD; DDaD Â 100), in the subjects with visceral type obesity (3.09 AE 0.43%) was signi®cantly lower than those of the subjects with subcutaneous type obesity and non-obese subjects (7.90 AE 0.51%, 8.91 AE 0.44%, respectively, P`0.01). The magnitude of endothelium-independent vasodilatation by nitroglycerin was similar in all groups. On multiple regression analysis, the PmaxaSmin showed a signi®cant inverse correlation with %FMD. CONCLUSIONS: The subjects with visceral type obesity, rather than those with the subcutaneous type, are associated with impaired¯ow-mediated endothelium-dependent vasodilatation of the brachial artery.

Abstract-Endothelial dysfunction has been reported to be the initial step in atherosclerosis. A noninvasive technique that uses ultrasound to measure the intima-media thickness of the carotid artery has been applied to evaluate localized atherosclerosis. This study was undertaken to elucidate whether endothelial dysfunction in the brachial artery is related to the intima-media thickness of the carotid artery. Thirty-four men with atherosclerosis (meanϮSE age 61Ϯ2 years) and 33 age-matched men without clinical atherosclerosis were examined. The intima-media thickness and plaque formation of the common carotid artery were assessed by B-mode ultrasonography. We also noninvasively measured brachial artery diameter by the same ultrasound machine when the subjects were at rest, during reactive hyperemia, which causes endothelium-dependent vasodilatation, and after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. The atherosclerosis group had a significantly greater intima-media thickness of the common carotid artery than did the control group (1.02Ϯ0.04 versus 0.91Ϯ0.03 mm, PϽ0.05). The flow-mediated diameter (FMD) increase (percent FMDϭ⌬D/Dϫ100) in the atherosclerosis group was significantly smaller than that in the control group (2.8Ϯ0.4% versus 5.1Ϯ0.6%, PϽ0.01). A significant negative correlation between the intima-media thickness of the carotid artery and percent FMD was found in all of the subjects. On multiple regression analysis, percent FMD showed a significant negative correlation with the intima-media thickness of the common carotid artery. These findings support the concept that endothelial dysfunction is significantly related to atherogenesis. Key Words: vasodilatation Ⅲ endothelium Ⅲ carotid artery Ⅲ atherosclerosis E vidence has accumulated that impairment of vascular endothelial function is the initial step in the development of atherosclerosis. 1 One important finding is the impaired release of endothelium-dependent relaxing factor, which is now thought to be NO or its related substances, from endothelial cells. 1 Flow-mediated dilatation (FMD) induced by reactive hyperemia has been known to be endothelium dependent, 2 and this phenomenon can be detected during reactive hyperemia by high-resolution ultrasound in superficial arteries. 3,4 Several coronary risk factors such as hypercholesterolemia, 5 smoking, 6 and hyperhomocysteinemia 4 have been reported to be significantly related to decreased FMD. However, no study has been reported to demonstrate an association between increased intima-media thickness (IMT) of the carotid artery and decreased FMD.A noninvasive technique that uses B-mode ultrasonography can visualize and assess the lumen and vessel wall of the carotid artery. We analyzed IMT of the right common carotid artery by using this method. 7 IMT thickening consists of both an intimal atherosclerotic process and medial hypertrophy. Because IMT is increased in subjects with familial hypercholesterolemia 8 and shows a progressive reduction with ch...

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ndothelial dysfunction is recognized as an early phase of arteriosclerosis 1 and an important cause of that dysfunction is impaired nitric oxide (NO) release from the endothelium. Endothelial NO is a key regulator of vascular homeostasis; it induces vasorelaxation by generating cyclic GMP in the underlying smooth muscle cells, and prevents monocyte adhesion to the endothelium, platelet activation, and smooth muscle cell proliferation. Hence, impaired NO release from injured endothelial cells is regarded as an initiator and promoter of arteriosclerosis.Endothelial NO is produced when L-arginine is con- February 2005 verted to L-citrulline by the enzyme endothelial nitric oxide synthase (eNOS). Endothelial NOS is inhibited by endogenous inhibitors, NG-monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA), which are structural analogues of L-arginine. 2,3 Plasma ADMA is eliminated by renal excretion and by degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). 4 Increased plasma concentration of ADMA is associated with hypertension, 5 pulmonary hypertension, 6 hypercholesterolemia, 7,8 carotid intima -media thickening, 9 severe peripheral artery occlusive disease, 10 and the clustering of coronary risk factors. 9 These findings suggest that ADMA is responsible for endothelial dysfunction. Obstructive sleep apnea syndrome (OSAS) has been recently attracting attention as a significant disorder. Frequent apnea/hypopnea attacks followed by arousal results in insufficient sleep at night, causing daytime sleepiness, leading to work inefficiency, and even traffic accidents. In addition, OSAS often accompanies hypertension, obesity, glucose intolerance, and dyslipidemia, all of which are factors in metabolic syndrome. Hence, OSAS is recognized as a risk factor for cardiovascular disease. 11-14 It has been Background Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease. Methods and ResultsIn the present study, flow-mediated vasodilatation (FMD) of the brachial artery and plasma concentrations of ADMA were measured before and after nasal continuous positive airway pressure (nCPAP) therapy, which abrogates apnea, in 10 male patients aged 36-69 years old, who were given a diagnosis of OSAS by polysomnography. The percent FMD (%FMD) improved significantly from 3.3±0.3% to 5.8±0.4% (p<0.01) and 6.6±0.3% (p<0.01), before, 1 week, and 4 weeks after nCPAP, respectively. At the same time, the plasma NOx concentrations, metabolites of NO, tended to increase, bu...