Phosphoinositide 3-kinase [gamma]/[delta] inhibition limits infarct size after myocardial ischemia/reperfusion injury

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 52; p. 19866
• Main Authors: Doukas, John, Wrasidlo, Wolfgang, Noronha, Glenn, Dneprovskaia, Elena
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 26.12.2006
• Subjects: Cells; DNA damage; Heart attacks; Inflammatory diseases; Kinases
• ISSN: 0027-8424; 1091-6490

Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (...) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory P13K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted P13K 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 P13K ... 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. (ProQuest Information and Learning: ... denotes formulae/symbols omitted.)