Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.
Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.
复制标题
阻断死亡检查点蛋白 TRAIL 可改善猴、猪和大鼠心肌梗死后的心功能
DOI：
10.1126/scitranslmed.aaw3172
复制
发表时间：
2020-04-22
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
TRAIL 阻断可限制心肌细胞死亡并减少炎症，从而改善大鼠、猪和猴子心肌梗塞后的心脏功能。抑制心肌细胞死亡 心肌梗塞引起的细胞死亡会导致心脏功能障碍和病理重塑。王等人。研究发现，在多种动物模型中，阻断肿瘤坏死因子相关凋亡诱导配体 (TRAIL)（死亡受体 5 (DR5) 的配体）可减少心肌梗塞后的炎症并改善心脏功能。在诱导缺血后 2 小时内用可溶性 DR5 融合蛋白治疗啮齿类动物、猪和猴子，可减少骨髓细胞向受损心脏组织的募集并减弱细胞死亡。 TRAIL 阻断可以在心肌梗塞的情况下提供潜在的心脏保护。心肌梗塞（MI）是全球范围内导致死亡的主要原因，且无法治愈。尽管心肌细胞死亡是众所周知的 MI 病理机制，但通过阻断细胞死亡来治疗 MI 并不简单。死亡受体 5 (DR5) 及其配体 TRAIL [肿瘤坏死因子 (TNF) 相关凋亡诱导配体] 在 MI 中表达上调，但它们在病理重塑中的作用尚不清楚。在这里，我们报告用可溶性 DR5 免疫球蛋白融合蛋白阻断 TRAIL，通过防止大鼠、猪和猴子的心肌细胞死亡和炎症来减少心肌梗死。从机制上讲，TRAIL诱导心肌细胞死亡并募集和激活白细胞，直接或间接引起心脏损伤。转录组分析显示梗塞心脏组织中炎症细胞因子的表达增加，而 TRAIL 阻断则显着降低炎症细胞因子的表达。总之，我们的研究结果表明，TRAIL 通过靶向心肌细胞直接介导 MI，并通过影响骨髓细胞间接介导 MI，支持 TRAIL 阻断作为治疗 MI 的潜在治疗策略。
TRAIL blockade limits cardiac cell death and reduces inflammation to improve cardiac function after myocardial infarction in rats, pigs, and monkeys. Curbing cardiac cell death Cell death resulting from myocardial infarction contributes to cardiac dysfunction and pathological remodeling. Wang et al. found that blocking tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a ligand of death receptor 5 (DR5), reduced inflammation and improved cardiac function after myocardial infarction in multiple animal models. Treating rodents, pigs, and monkeys with a soluble DR5 fusion protein within 2 hours after inducing ischemia reduced recruitment of myeloid cells to injured heart tissue and blunted cell death. TRAIL blockade could offer potential cardiac protection in the setting of myocardial infarction. Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)–related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.
登录
查看更多内容
影响因子：
3.8
作者：
Fan, Lianchun;Kadura, Ibrahim;Frye, Christopher C.
通讯作者：
Frye, Christopher C.
影响因子：
5.4
作者：
Fink, Katja;Ng, Cedrig;Schul, Wouter
通讯作者：
Schul, Wouter
影响因子：
4.5
作者：
Harith, Hanis H.;Di Bartolo, Belinda A.;Kavurma, Mary M.
通讯作者：
Kavurma, Mary M.
DOI：
10.1016/j.bbrc.2010.07.082
发表时间：
2010-08-27
影响因子：
3.1
作者：
Jeong, Jae-Kyo;Moon, Myung-Hee;Lee, You-Jin
通讯作者：
Lee, You-Jin
DOI：
10.1016/0735-1097(94)00443-t
发表时间：
1995-03-01
影响因子：
24
作者：
AVERSANO, T;ZHOU, W;WEISMAN, H
通讯作者：
WEISMAN, H