• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury
【24h】

Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury

机译：磷酸肌醇3激酶γ/δ抑制作用可限制心肌缺血/再灌注损伤后的梗塞面积

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (γ and δ) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreac-tive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K γ/δ inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothefial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the post-reperfusion time period.
机译：尽管磷酸肌醇3-激酶（PI3K）在组织缺血过程中发挥有益的前细胞存活作用，但某些同工型（γ和δ）矛盾地促成炎症，在再灌注时会损伤这些相同的组织。因此，我们认为在再灌注阶段选择性抑制促炎性PI3K亚型可能最终限制了局部缺血/再灌注损伤（如心肌梗塞）中的整体组织损伤。通过筛选一个新的化学家族来鉴定全反应性和同工型限制的PI3K抑制剂。分子建模研究基于取代基团的旋转自由度将同工型特异性归因于。一种化合物（TG100-115）被鉴定为选择性PI3Kγ/δ抑制剂，可响应已知参与心肌梗塞的多种介体，包括血管内皮生长因子和血小板活化因子，有效抑制水肿和炎症。相比之下，内皮细胞的有丝分裂是对缺血损伤后组织存活重要的修复过程，没有被破坏。在严格的动物MI模型中，TG100-115提供了有效的心脏保护作用，减少了梗塞的发展并保持了心肌功能。重要的是，这是在心肌再灌注后（最多3小时），即患者最易接受治疗干预的同一时间给药时实现的。总之，通过针对在心肌损害中相对较晚发生的病理事件，我们确定了解决难以实现的临床目标的潜在手段：在再灌注后的时期内有意义的心脏保护。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号