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GW24-e3751 Oxidative stress-dependent cyclooxygenase 2-derived vasoconstrictive prostaglandins contribute to hyperhomocysteinemia-induced endothelial dysfunction in hyperlipidemia
  1. Zhongjian Cheng,
  2. Xiaohua Jiang,
  3. William Durante,
  4. Warren D Kruger,
  5. Xiaofeng Yang,
  6. Hong Wang
  1. Temple University, Philadelphia, PA 19140

Abstract

Objectives We recently reported that elevation of plasma homocysteine level—hyperhomocysteinemia (HHcy) accelerates atherosclerosis and vascular inflammation in hyperlipidemia. Prostanoids are local mediators of inflammation and are synthesised from arachidonic acid by cycloxygenase (COX). In this study, we examined the role of COX2 which is cytokine-inducible and highly expressed in vasculature inresponsible to inflammation, in HHcy-induced endothelial dysfunction (ED) in hyperlipidemia.

Methods Endothelial function was assessed in the thoracic aorta from a novel severe HHcy (PlasmaHcy = 221 μM) mouse model: human cystathionine β-synthase (CBS) transgenic, mouse CBS and apolipoprotine E gene deficient mouse (hTgCBS_mApoE-/-/Cbs-/-) fed a high fat diet for 8 weeks.

Results Endothelium-dependentrelaxation to acetylcholine (ACh) was significantly impaired in the aorta of hTgCBS_ mApoE-/-/Cbs-/- mice compared with that of hTgCBS_mApoE-/-/Cbs+/+mice. Endothelium-independent vascular relaxation response to sodium nitroprusside was not changed. N(G)-nitro-L-Arg-methyl ester (L-NAME, eNOS inhibitor), abolished the relaxation responses to ACh in the aorta of hTgCBS_mApoE-/-/Cbs-/- mice but not in that of hTgCBS, mApoE-/-/Cbs+/+ mice. L-NAME plus COX1/2 inhibitor indomethacin (INDO) completely blocked relaxation response to ACh in the aorta from both HHcy and control mice, indicating that COX plays a major role in HHcy-induced ED in hyperlipidemia. Moreover, INDO, COX2 inhibitor nimesulide, and thromboxane A2/prostaglandin H2 receptor antagonist SQ29548, but not COX1 inhibitor SC560, improved HHcy-aggravated ED inhyperlipidemia, indicating that COX2, but not COX1, contributes to HHcy-induced ED in hyperlipidemia. In addition, preincubation the aorta with antioxidants Tempol (a superoxide scavenger), polyethylene glycol-tagged superoxide dismutase (PEG-SOD) and apocynin also improved HHcy-induced ED in hyperlipidemia. By immunohistochemistry, HHcy markedly increased protein expression of COX2 and 3-nitrotyrosin (3-NT)—a foot print of superoxide, but not COX1, in the endothelium of aorta. By Weston blot, HHcy induced inflammatory factors including ICAM-1, VCAM-1, and TNFα in the aorta extract from the mice with hyperlipidemia. Moreover, COX2, but not COX1, and 3-NT was markedly increased in cultured human aorticendothelial cells treated with a combination of DL-Hcy (500 μM) and oxidised-LDL(200 µg/ml) for 48 hours compared to that treated with either DL-Hcy oroxidized-LDL alone. DL-Hcy/oxidased-LDL-induced COX2 was prevented by PEG-SOD. Finally, HHcy markedly accelerated urinary 2, 3-dinor TXB2, TXB2,8-isoprostan and 6-keto prostaglandin F levels in hyperlipidemia.

Conclusions Severe HHcy causes ED in hyperlipidemia via oxidative stress-dependent COX2-derived vasoconstrictive prostaglandins.

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