Objective-We explored the effect of hydrogen sulfide (H 2 S) on atherosclerotic progression, particularly on intracellular adhesion molecule-1 (ICAM-1) in apolipoprotein-E knockout (apoE Ϫ/Ϫ ) mice and human umbilical vein endothelial cells (HUVECs). Methods and Results-ApoEϪ/Ϫ mice were treated with sodium hydrosulfide (NaHS) or DL-propargylglycine (PPG); HUVECs were pretreated with NaHS. Compared with control mice, apoE Ϫ/Ϫ mice showed decreased plasma H 2 S level and aortic H 2 S production but increased plasma ICAM-1 and aortic ICAM-1 protein and mRNA. Compared with apoE Ϫ/Ϫ mice, apoE Ϫ/Ϫ ϩNaHS mice showed increased plasma H 2 S level, but decreased size of atherosclerotic plaque and plasma and aortic ICAM-1 levels, whereas apoE Ϫ/Ϫ ϩPPG mice showed decreased plasma H 2 S level but enlarged plaque size and increased plasma and aortic ICAM-1 levels. NaHS suppressed ICAM-1 expression in tumor necrosis factor (TNF)-␣-treated HUVECs. NaHS inhibited IB degradation and NF-B nuclear translocation in HUVECs treated with TNF-␣. Ⅲapolipoprotein E knockout mice Ⅲ human umbilical vein endothelial cells A therosclerosis is an important underlying pathology of cardiovascular diseases, the leading cause of morbidity and mortality in many countries. Over the past 50 years, numerous studies attempting to explain the complex events leading to atherosclerosis have been undertaken. Nitric oxide and carbon monoxide, which are small gaseous transmitters, freely permeable to membrane, endogenously and enzymatically generated, and have specific functions, are recommended as gasotransmitters. 1 They have been closely implicated in endothelial dysfunction and vascular remodeling in atherosclerotic arteries; researches into the two gasotransmitters have improved the understanding of atherogenesis. [2][3][4][5] However, the mechanisms of atherosclerosis have not been fully elucidated. Conclusions-The

endothelial cells ͉ arachidonic acid ͉ AP-1 ͉ promoter ͉ hypertension A rachidonic acid (AA) derived from membrane phospholipids plays a key role in vascular inflammatory and/or antiinflammatory responses. AA can be converted to eicosanoids by three major enzymatic pathways, namely, cyclooxygenase, lipoxygenase, and CYP 450 epoxygenase. Exerting autocrine effects on vascular endothelial cells (ECs), four epoxyeicosatrienoic acids (EETs) regioisomers 5,6-, 8,9-, 11,12-, and 14,15-EET are the major metabolites generated by CYP 450 epoxygenase (1). EETs can be released by ECs to act as paracrine mediators on neighboring cells such as vascular smooth muscle cells (VSMCs) (2). EETs exert membrane potential-independent effects and modulate several signaling cascades that affect EC proliferation and angiogenesis. EETs also function as endothelium-derived hyperpolarizing factors (3). By increasing intracellular Ca 2ϩ concentration, EETs activate large conductance Ca 2ϩ -activated K ϩ channel (BK Ca ) in the smooth muscle. The activation of BK Ca then causes hyperpolarization of VSMCs and subsequent vasodilation, which lowers the blood pressure (4). As well, EETs inhibit cytokine-induced inflammatory responses in ECs (5, 6). Treating ECs with 11,12-EET or overexpression of CYP2J2 attenuated the TNF␣-, IL-1␣-, and LPSinduced expression of adhesion molecules in ECs, thus decreasing leukocyte adhesion to the vascular wall (7).Epoxide hydrolases (EHs) convert epoxides to the corresponding diols. Under physiological conditions, EETs can be enzymatically hydrolysed to dihydroxyeicosatrienoic acids (DHETs) by EHs (1). Two major EHs in the ␣/␤ hydrolase family exist in mammalian cells: soluble EH (sEH), which primarily presents in the cytosol and peroxisomes, and microsomal EH, which binds to the intracellular membranes (8). Highly expressed in the liver, kidney, intestine, and vasculature, sEH is the main enzyme that converts 5,8,11,14,8,11,14, respectively. The mammalian sEH is a homodimer, and each subunit contains a C-and an N-terminal domain. The active site is located in the C-terminal domain in which the residues Asp-333, Asp-495, and His-523 form the catalytic triad (9). DHETs are much more polar than EETs and are generally considered as biologically inactive products of EETs. However, their roles are not fully understood.Angiotensin II (Ang II), a potent vessel constrictor, elevates blood pressure in various animal models. i.p. injection of sEHselective inhibitors to Ang II-infused hypertensive rats greatly increased the level of EETs and lowered systolic blood pressure (10). Thus, augmentation of EET levels with enhanced production by CYP450s or decreased hydrolysis by sEH seems to control blood pressure in vivo. In line with this hypothesis, recent studies demonstrated that the selective sEH inhibitor Ncyclohexyl-N-dodecyl urea reversed the hypertensive phenotype in the spontaneously hypertensive rat (SHR) (11).We have previously shown that laminar shear stress, an atheroprotective flow, decreased the expression of sE...

These data provide direct evidence that Cat S plays an important role in AAA formation and suggest that Cat S is a new therapeutic target for human AAA.

The mechanisms responsible for the cardioprotective effect of hydrogen sulfide (H(2)S) are unclear. The present study was designed to examine whether H(2)S could regulate hyperhomocysteinemia (HHcy)-induced cardiomyocytic endoplasmic reticulum (ER) stress. A rat model of HHcy was produced, and H9c2 cells (rat embryonic heart-derived cell line) were cultured. The plasma homocysteine was measured by using HPLC. Plasma H(2)S concentration and myocardial H(2)S production were measured with a sulfide-sensitive electrode. Confocal immunofluorescent analysis for cardiomyocytic C/EBP homologous protein (CHOP) was performed. Glucose-regulated protein 78 (GRP78), CHOP, and caspase 12 expressions by myocardial tissues and cleaved caspase 12 and p-eIF2alpha expressions by H9c2 cells were detected with Western blotting. The results showed that methionine overload induced HHcy, resulting in a marked cardiomyocytic ER stress, whereas endogenous production of H(2)S was reduced in rats with HHcy. H(2)S supplementation, however, decreased expressions of ER stress-associated proteins, including GRP78, CHOP, and caspase 12, by myocardial tissues in vivo. The inhibition of endogenous H(2)S production further enhanced cardiomyocytic ER stress, but H(2)S supplementation effectively antagonized the H9c2 cell CHOP, cleaved caspase 12 and p-eIF2alpha expressions induced by Hcy, thapsigargin, or tunicamycin in vitro. The results suggest that H(2)S can attenuate cardiomyocytic ER stress in HHcy-induced cardiomyocytic injury.