Marchetti Carlo, Chojnacki Jeremy, Toldo Stefano, Mezzaroma Eleonora, Tranchida Nicla, Rose Scott W, Federici Massimo, Van Tassell Benjamin W, Zhang Shijun, Abbate Antonio
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
Victoria Johnson Research laboratories, Virginia Commonwealth University, Richmond, VA, USA.
J Cardiovasc Pharmacol. 2014 Apr;63(4):316-322. doi: 10.1097/FJC.0000000000000053.
The formation of the NLRP3 inflammasome in the heart during acute myocardial infarction amplifies the inflammatory response and mediates further damage. Glyburide has NLRP3 inhibitory activity in vitro but requires very high doses in vivo, associated with hypoglycemia. The aim of this study was to measure the effects on the NLRP3 inflammasome of 16673-34-0, an intermediate substrate free of the cyclohexylurea moiety, involved in insulin release.
We synthesized 16673-34-0 (5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]benzamide) that displayed no effect on glucose metabolism. HL-1 cardiomyocytes were treated with lipopolysaccharide and ATP to induce the formation of the NLRP3 inflammasome, measured as increased caspase-1 activity and cell death, and 16673-34-0 prevented such effects. 16673-34-0 was well tolerated with no effects on the glucose levels in vivo. Treatment with 16673-34-0 in a model of acute myocardial infarction because of ischemia and reperfusion significantly inhibited the activity of inflammasome (caspase-1) in the heart by 90% (P < 0.01) and reduced infarct size, measured at pathology (by >40%, P < 0.01) and with troponin I levels (by >70%, P < 0.01).
The small molecule 16673-34-0, an intermediate substrate in the glyburide synthesis free of the cyclohexylurea moiety, inhibits the formation of the NLRP3 inflammasome in cardiomyocytes and limits the infarct size after myocardial ischemia-reperfusion in the mouse, without affecting glucose metabolism.
急性心肌梗死期间心脏中NLRP3炎性小体的形成会放大炎症反应并介导进一步损伤。格列本脲在体外具有NLRP3抑制活性，但在体内需要非常高的剂量，且与低血糖有关。本研究的目的是测量16673-34-0（一种参与胰岛素释放且不含环己基脲部分的中间底物）对NLRP3炎性小体的影响。
我们合成了16673-34-0（5-氯-2-甲氧基-N-[2-(4-氨磺酰基苯基)乙基]苯甲酰胺），其对葡萄糖代谢无影响。用脂多糖和ATP处理HL-1心肌细胞以诱导NLRP3炎性小体的形成，通过半胱天冬酶-1活性增加和细胞死亡来衡量，而16673-34-0可预防此类影响。16673-34-0耐受性良好，对体内葡萄糖水平无影响。在缺血再灌注引起的急性心肌梗死模型中，用16673-34-0治疗可使心脏中炎性小体（半胱天冬酶-1）的活性显著抑制90%（P<0.01），并减小梗死面积，通过病理学测量（减少>40%，P<0.01）以及肌钙蛋白I水平（降低>70%，P<0.01）。
小分子16673-34-0是格列本脲合成中不含环己基脲部分的中间底物，可抑制心肌细胞中NLRP3炎性小体的形成，并限制小鼠心肌缺血再灌注后的梗死面积，且不影响葡萄糖代谢。
