Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury
Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury
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DOI：
10.1073/pnas.0606956103
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发表时间：
2006-12-26
影响因子：
11.1
通讯作者：
Cheresh, David
中科院分区：
文献类型：
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作者：
Doukas, John;Wrasidlo, Wolfgang;Cheresh, David
尽管磷酸肌肽3-激酶（pi3k）在组织缺血过程中发挥着有益的促细胞存活作用，但一些亚型（γ和δ）却矛盾地促进了再灌注时损伤这些组织的炎症。因此，我们考虑在再灌注阶段选择性抑制促炎PI3K亚型的可能性，可能最终限制缺血/再灌注损伤（如心肌梗死）中出现的整体组织损伤。通过筛选一个新的化学家族，确定了泛反应性和同型限制性PI3K抑制剂；分子模型研究将异构体的特异性归因于取代基的旋转自由度。一种化合物（TG100-115）被确定为选择性PI3K γ / δ抑制剂，对多种已知参与心肌梗死的介质，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，内皮细胞有丝分裂，一个对缺血损伤后组织存活很重要的修复过程，没有被中断。在严格的动物心肌梗死模型中，TG100-115提供了有效的心脏保护，减少梗死发展并保持心肌功能。重要的是，这是在心肌再灌注后（最多3小时后）给药时实现的，这段时间是患者最容易接受治疗干预的时间。总之，通过靶向发生在心肌损伤相对较晚的病理事件，我们已经确定了一种潜在的方法来解决一个难以捉摸的临床目标：在灌注后时间段内实现有意义的心脏保护。
Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (gamma and delta) 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. Panreactive 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 gamma/delta 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, endothelial 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 postreperfusion time period.