State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital Medical School of Nanjing University Nanjing China.
J Am Heart Assoc. 2022 Jul 5;11(13):e025266. doi: 10.1161/JAHA.122.025266. Epub 2022 Jun 29.
Background Dilated cardiomyopathy remains a leading cause of heart failure worldwide. Immune inflammation response is recognized as a significant player in the progression of heart failure; however, immunomodulatory strategies remain a long-term challenge. Colchicine, a potent anti-inflammatory drug, has many benefits in ischemic cardiovascular events, but its role in nonischemic heart failure remains unclear. Methods and Results Doxorubicin administration was used to establish a murine dilated cardiomyopathy model, and colchicine or saline was orally given. At the end point, cardiac function and fibrosis were measured to investigate the effects of colchicine. Inflammatory cytokine levels, neutrophil recruitment, and NLRP3 (NOD-like receptor protein 3) inflammasome activation were detected to evaluate the inflammatory response. Furthermore, to examine the downstream target of colchicine, SIRT2 (Sirtuin 2) was pharmacologically inhibited in vitro; thus, changes in the NLRP3 inflammasome were detected by immunoblotting. These results showed that murine cardiac function was significantly improved and fibrosis was significantly alleviated after colchicine treatment. Moreover, the infiltration of neutrophils and the levels of inflammatory cytokines in the failing myocardium were both decreased by colchicine treatment. Mechanistically, colchicine upregulated the expression of SIRT2, leading to the inactivation of the NLRP3 inflammasome in an NLRP3 deacetylated manner. Conversely, the inhibition of SIRT2 attenuated the suppressive effect of colchicine on NLRP3 inflammasome activation. Conclusions This study indicated that colchicine could be a promising therapeutic candidate for dilated cardiomyopathy and other nonischemic heart failure associated with the inflammatory response.
扩张型心肌病仍然是全球心力衰竭的主要原因。免疫炎症反应被认为是心力衰竭进展的重要因素；然而，免疫调节策略仍然是一个长期挑战。秋水仙碱是一种有效的抗炎药物，在缺血性心血管事件中有许多益处，但它在非缺血性心力衰竭中的作用仍不清楚。
用阿霉素建立了小鼠扩张型心肌病模型，并给予秋水仙碱或生理盐水口服。在终点时，测量心功能和纤维化，以研究秋水仙碱的作用。检测炎症细胞因子水平、中性粒细胞募集和 NLRP3（NOD 样受体蛋白 3）炎性小体激活，以评估炎症反应。此外，为了研究秋水仙碱的下游靶点，在体外药理学抑制 SIRT2（沉默信息调节因子 2）；因此，通过免疫印迹检测 NLRP3 炎性小体的变化。结果表明，秋水仙碱治疗后，小鼠心功能明显改善，纤维化明显减轻。此外，秋水仙碱治疗还降低了衰竭心肌中中性粒细胞的浸润和炎症细胞因子的水平。机制上，秋水仙碱上调了 SIRT2 的表达，导致 NLRP3 炎性小体以 NLRP3 去乙酰化的方式失活。相反，SIRT2 的抑制减弱了秋水仙碱对 NLRP3 炎性小体激活的抑制作用。
本研究表明，秋水仙碱可能是扩张型心肌病和其他与炎症反应相关的非缺血性心力衰竭的有前途的治疗候选药物。
