PMID- 27894813 OWN - NLM STAT- MEDLINE DCOM- 20170405 LR - 20220310 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 794 DP - 2017 Jan 5 TI - Salicylic acid retention impairs aspirin reactivity in type 2 diabetes. PG - 234-245 LID - S0014-2999(16)30756-7 [pii] LID - 10.1016/j.ejphar.2016.11.042 [doi] AB - High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain elusive. The objective of this study was to uncover the potential link between pathogenic accumulation of salicylic acid (SA), the major metabolite of aspirin, and HAPR in diabetic state. Aspirin failed to inhibit platelet CD62P expression and thromboxane (TX) B(2)/6-keto-prostaglandin（PG）F(1alpha) ratio in a type 2 diabetes mellitus (T2DM) mice model, particularly in the female, which were unanimously accompanied by significantly higher plasma SA concentrations. Pre-administration with SA increased both platelet CD62P expression and TXB(2)/6-keto-PGF(1alpha) ratio in female T2DM mice, while pretreatment with NaHCO(3) caused the opposite effect. On the in vitro human umbilical vein endothelial cells (HUVECs)-platelet interaction assay, SA suppressed inflammation-induced cyclooxygenase-2 upregulation on HUVECs and attenuated their inhibitory effect on platelet aggregation in a dose-dependent manner. The prolonged retention of SA in diabetes may be partially explained by the downregulation of various SA efflux transporters in the kidney and the decreased urine pH. Importantly, in female aspirin non-responsive patients, the trough plasma concentration of SA are markedly increased with T2DM treated with long-term aspirin, and TXB(2)/6-keto-PGF(1alpha) ratio and uric acid level in plasma are positively correlated with SA concentration. Our findings support that the accumulation of SA represents an important factor in causing HAPR in diabetes, and that targeting impaired SA excretion may become a novel intervention strategy to diabetes-associated HAPR. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Zhang, Haowen AU - Zhang H AD - First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China; Department of Cardiology, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, QinHuai District, Nanjing 210029, China. FAU - Xie, Hao AU - Xie H AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China. FAU - Zheng, Xiao AU - Zheng X AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China; Department of Pharmacy, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing, China. FAU - Chai, Yingying AU - Chai Y AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China. FAU - Tang, Zhiyuan AU - Tang Z AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China. FAU - Chen, Hanyu AU - Chen H AD - First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China; Department of Cardiology, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, QinHuai District, Nanjing 210029, China. FAU - Li, Feiyan AU - Li F AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China. FAU - Christoph, Heier AU - Christoph H AD - Institute of Molecular Biosciences, University of Graz, Graz, Austria. FAU - Chen, Jiandong AU - Chen J AD - Department of Cardiology, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, QinHuai District, Nanjing 210029, China. FAU - Sun, Weixin AU - Sun W AD - First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China; Department of Cardiology, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, QinHuai District, Nanjing 210029, China. FAU - Ye, Hui AU - Ye H AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China. FAU - Wang, Shiguang AU - Wang S AD - First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China; Department of Cardiology, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, QinHuai District, Nanjing 210029, China. FAU - Hao, Haiping AU - Hao H AD - State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China. Electronic address: hhp_770505@hotmail.com. FAU - Chen, Xiaohu AU - Chen X AD - Department of Cardiology, Jiangsu Province Hospital of Traditional Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, QinHuai District, Nanjing 210029, China. Electronic address: chenxhdoctor@126.com. LA - eng PT - Journal Article DEP - 20161125 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Interleukin-1beta) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - O414PZ4LPZ (Salicylic Acid) RN - R16CO5Y76E (Aspirin) SB - IM MH - Aged MH - Animals MH - Aspirin/*pharmacology MH - Cyclooxygenase 2/metabolism MH - Diabetes Mellitus, Type 2/blood/*metabolism/physiopathology MH - Female MH - Gene Expression Regulation, Enzymologic/drug effects MH - Human Umbilical Vein Endothelial Cells/drug effects/metabolism MH - Humans MH - Interleukin-1beta/pharmacology MH - Kidney/drug effects/metabolism MH - Male MH - Mice MH - Platelet Aggregation/drug effects MH - Retrospective Studies MH - Salicylic Acid/blood/*metabolism/pharmacokinetics OTO - NOTNLM OT - Cyclooxygenase-2 OT - Diabetes OT - HAPR OT - Platelet OT - Salicylic acid EDAT- 2016/11/30 06:00 MHDA- 2017/04/06 06:00 CRDT- 2016/11/30 06:00 PHST- 2016/09/19 00:00 [received] PHST- 2016/11/22 00:00 [revised] PHST- 2016/11/24 00:00 [accepted] PHST- 2016/11/30 06:00 [pubmed] PHST- 2017/04/06 06:00 [medline] PHST- 2016/11/30 06:00 [entrez] AID - S0014-2999(16)30756-7 [pii] AID - 10.1016/j.ejphar.2016.11.042 [doi] PST - ppublish SO - Eur J Pharmacol. 2017 Jan 5;794:234-245. doi: 10.1016/j.ejphar.2016.11.042. Epub 2016 Nov 25.