title: Salicylic acid retention impairs aspirin reactivity in type 2 diabetes.
abstract: 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) B2/6-keto-prostaglandin（PG）F1αratio 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 TXB2/6-keto-PGF1αratio in female T2DM mice, while pretreatment with NaHCO3caused 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 TXB2/6-keto-PGF1αratio 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.
authors.affiliation: 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.
authors.forename: Haowen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chai
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Hanyu
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Heier
authors.initials: H
authors.lastname: Christoph
authors.affiliation: 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.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Weixin
authors.initials: W
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjiaxiang, Gulou District, Nanjing 210009, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: 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.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D012189:Retrospective Studies; D020156:Salicylic Acid / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D053583:Interleukin-1beta; D051546:Cyclooxygenase 2; D020156:Salicylic Acid; D001241:Aspirin
keywords: Cyclooxygenase-2; Diabetes; HAPR; Platelet; Salicylic acid