PMID- 25149102 OWN - NLM STAT- MEDLINE DCOM- 20141121 LR - 20140922 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 91 IP - 4 DP - 2014 Oct 15 TI - Cyclooxygenase-2-dependent oxidative stress mediates palmitate-induced impairment of endothelium-dependent relaxations in mouse arteries. PG - 474-82 LID - S0006-2952(14)00464-X [pii] LID - 10.1016/j.bcp.2014.08.009 [doi] AB - Palmitic acid, one of the saturated free fatty acids, impairs cardiovascular function as manifested by inducing vascular inflammation, apoptosis and over-production of reactive oxygen species (ROS) although the origin for ROS remains unclear. The present study investigated the cellular mechanisms underlying palmitate-induced impairment of endothelial function. Ex vivo treatment in tissue culture with palmitate concentration-dependently attenuated acetylcholine-induced endothelium-dependent relaxations, up-regulated the expression of cyclooxygenase-2 (COX-2) and elevated superoxide formation in mouse aortic endothelial cells (MAECs) measured by dihydroethidium (DHE) staining and electron paramagnetic resonance (EPR) spectroscopy. Superoxide scavengers, COX-2 inhibitor and thromboxane prostanoid (TP) receptor antagonist, but not COX-1 inhibitor reversed the harmful effects of palmitate. Furthermore, palmitate impaired acetylcholine-induced relaxations and raised superoxide in en face endothelium of aortas only from COX-1(-/-) mice but not from COX-2(-/-) mice. Palmitate increased the production and release of TXB2, a stable thromboxane A2 metabolite in mouse aortas, which was abolished by COX-2 inhibitor. Superoxide scavenger did not affect palmitate-induced up-regulated expression of COX-2 in MAECs. Both real time PCR and luciferase reporter gene assay confirmed COX-2 up-regulation in palmitate-treated MAECs and NF-kappaB was substantially involved in this up-regulation. The present study provides novel evidence that palmitate up-regulates COX-2 through NF-kappaB-dependent mechanism and resultant COX-2-associated oxidative stress impairs endothelium-dependent relaxations in mouse aortas. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Gao, Zhen AU - Gao Z AD - Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Zhang, Huina AU - Zhang H AD - Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. FAU - Liu, Jian AU - Liu J AD - Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Lau, Chi Wai AU - Lau CW AD - Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Liu, Pingsheng AU - Liu P AD - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. FAU - Chen, Zhen Yu AU - Chen ZY AD - School of Life Sciences, Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Lee, Hung Kay AU - Lee HK AD - Department of Chemistry, Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Tipoe, George L AU - Tipoe GL AD - Department of Anatomy, University of Hong Kong, Hong Kong SAR, China. FAU - Ho, Hing Man AU - Ho HM AD - School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. FAU - Yao, Xiaoqiang AU - Yao X AD - Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China. FAU - Huang, Yu AU - Huang Y AD - Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: yu-huang@cuhk.edu.hk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140819 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 11062-77-4 (Superoxides) RN - 2V16EO95H1 (Palmitic Acid) RN - EC 1.14.99.1 (Cyclooxygenase 2) SB - IM MH - Animals MH - Arteries/*drug effects/enzymology/metabolism MH - Cyclooxygenase 2/*metabolism MH - Electron Spin Resonance Spectroscopy MH - Endothelium, Vascular/*drug effects/enzymology/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Muscle Relaxation/drug effects MH - *Oxidative Stress MH - Palmitic Acid/*pharmacology MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - Superoxides/metabolism OTO - NOTNLM OT - A23187 (PubChem CID: 11957499) OT - Acetylcholine (PubChem CID: 187) OT - Celecoxib (PubChem CID: 2662) OT - Cyclooxygenase-2 OT - DMPO (PubChem CID: 1774) OT - DTPA (PubChem CID: 3053) OT - Dihydroethidium (PubChem CID: 128682) OT - Endothelium-dependent relaxations OT - Hypoxanthine (Pubchem CID:790) OT - L-NAME (PubChem CID 39836) OT - Palmitate OT - Parthenolide (PubChem CID: 6473881) OT - Phenylephrine (PubChem CID: 6041) OT - S18886 (PubChem CID: 9938840) OT - SC-560 (PubChem CID: 4306515) OT - Sodium palmitate (PubChem CID: 2735111) OT - Superoxide OT - TEMPONE-H (PubChem CID: 98642) OT - Tempol (PubChem CID: 137994) OT - Thromboxane B2 (Pubchem CID: 5283137) OT - Vitamin E (PubChem CID: 2116) EDAT- 2014/08/26 06:00 MHDA- 2014/12/15 06:00 CRDT- 2014/08/24 06:00 PHST- 2014/05/20 00:00 [received] PHST- 2014/08/06 00:00 [revised] PHST- 2014/08/06 00:00 [accepted] PHST- 2014/08/24 06:00 [entrez] PHST- 2014/08/26 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] AID - S0006-2952(14)00464-X [pii] AID - 10.1016/j.bcp.2014.08.009 [doi] PST - ppublish SO - Biochem Pharmacol. 2014 Oct 15;91(4):474-82. doi: 10.1016/j.bcp.2014.08.009. Epub 2014 Aug 19.