Salicylic acid renders aspirin resistance via breaking the functional balance of COX-1/COX-2 in diabetic mice
Aspirin resistance (AR) has become a serious clinical concern.Diabetes is an established risk factor of At, but the key mechanisms remain elusive.Herein, we show that salicylic acid (SA),the major metabolite of aspirin, critically contributes to AR in diabetic mice by disrupting the functional balance of endothelial COX-1 and COX-2.Diabetic state induced by high-fat diet and streptomycin leads to a significant retention of SA in mice receiving aspirin (40 mg/kg) for a week,partially due to impaired renal excretion by organic anion transporter1 and 3 (OAT1, OAT3),sodium-coupled monocarboxylate transporter 1(SMCT1) and uric acid transporter 1(URAT1).Oral administration of SA to diabetic mice exacerbates AR, as indicated by a remarkable increase in platelet P-selection (CD62P).Moreover, blunting SA accumulation by sodium biocarbonate efficiently attenuates AR in diabetic mice.High-level SA in the circulation abrogates the compensatory unregulation of endothelial COX-2 in diabetic mice, decreases 6-keto-prostaglandin (PG) F1α/ thromboxane (TX) B2 ratio, thereby precipitating the platelet activation toward aggregation.Taken together, our results uncover diabetes-associated SA accumulation as a previously unappreciated player for high AR incidence in the context of diabetes, and we propose that diabetes-induced impairment of SA transport might be a novel target to combat AR.
Haowen Zhang Yingying Chai Hao Xie Hanyu Chen Xiao Zheng Jiandong chen Lin Wang Haiping Hao Xiaohu Chen
First Clinical Medical College,Nanjing University of Chinese Medicine,Nanjing 210023,China;Departmen State Key Laboratory of Natural Medicines,Key Lab of Drug Metabolism and Pharmacokinetics,China Phar Department of Pharmacy,Jiangsu Province Hospital of Traditional Chinese Medicine,Nanjing 210029,Chin Department of Cardiology,Jiangsu Province Hospital of Traditional Chinese Medicine,the Affiliated Ho
国内会议
中国中西医结合学会心血管病专业委员会动脉粥样硬化与血脂异常诊治研讨会
乌鲁木齐
英文
170-187
2015-06-12（万方平台首次上网日期，不代表论文的发表时间）