benzofurans and acetovanillone

We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H₂O₂, leading to endothelium-dependent dilation. In contrast, thromboxane A₂ (TXA₂), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-H₂O₂ pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) TXA₂ contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX = LDLR(-/-); hApoB(+/+)) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H₂O₂ production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-H₂O₂ pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA₂ with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-H₂O₂ pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA₂ synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA₂ production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA₂ on the control of cerebral tone and maintained eNOS function.

Topics: Acetophenones; Aging; Animals; Antioxidants; Atherosclerosis; Benzofurans; Catechin; Cerebral Arteries; Enzyme Inhibitors; Hemodynamics; Humans; Hydrogen Peroxide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Oxidants; Oxidative Stress; Receptors, LDL; Thromboxane A2; Thromboxane-A Synthase; Up-Regulation

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Tumor necrosis factor-alpha (TNF-alpha) enhances NAD (P) H oxidase-dependent reactive oxygen species (ROS) formation and ROS induce MMP-2. In the present study, the effects of a potent water-soluble antioxidant, salvianolic acid B (SalB), derived from a Chinese herb, Salvia miltiorrhiza, on the expression of MMP-2 by TNF-alpha-treated human aortic smooth muscle cells (HASMCs) were investigated. In this study, salvianolic acid B scavenged H2O2 in a dose-dependent manner in test tube. We found that SalB, as well as NADPH oxidase inhibitors, DPI or apocynin, and antioxidant NAC, inhibited TNF-alpha-induced MMP-2 mRNA, protein expression, and gelatinolytic activity in HASMCs in a concentration-dependent manner. We also observed a dose-dependent decrease in ROS production and NADPH oxidase activity induced by TNF-alpha in the presence of SalB. SalB also significantly inhibited angiotensin II or H2O2-induced MMP-2 mRNA and protein expression and gelatinolytic activity in HASMCs. Our data point out that the importance of NADPH oxidase-dependent ROS generation in the control of SalB inhibition of TNF-alpha-induced MMP-2 expression and activity.

Topics: Acetophenones; Acetylcysteine; Angiotensin II; Aorta; Benzofurans; Cells, Cultured; Humans; Hydrogen Peroxide; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; NADPH Oxidases; Onium Compounds; Reactive Oxygen Species; Salvia miltiorrhiza; Tumor Necrosis Factor-alpha; Up-Regulation