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

Background:
Phosphoinositide 3-kinases (PI3Ks) are known to support cell survival during ischemic events; however, certain isoforms—specifically PI3Kγ and PI3Kδ—also promote inflammatory responses that exacerbate tissue damage during reperfusion. This paradox led us to investigate whether selective inhibition of these proinflammatory PI3K isoforms during the reperfusion phase could reduce tissue injury in ischemia/reperfusion conditions such as myocardial infarction (MI).

Methods and Results:
A novel chemical library was screened to identify both pan-PI3K and isoform-selective inhibitors. Structure-based modeling linked isoform selectivity to the rotational flexibility of specific substituent groups. One compound, TG100-115, emerged as a selective PI3Kγ/δ inhibitor. TG100-115 effectively suppressed inflammation and edema triggered by key mediators implicated in MI, including vascular endothelial growth factor (VEGF) and platelet-activating factor (PAF). Notably, it did not interfere with endothelial cell mitogenesis, a critical process for tissue repair after ischemia.

In established animal models of MI, TG100-115 demonstrated strong cardioprotective effects—significantly reducing infarct size and preserving myocardial function. Importantly, these benefits were observed even when the compound was administered up to three hours after reperfusion, aligning with the therapeutic window typically available in clinical settings.

Conclusions:
Selective inhibition of PI3Kγ/δ during reperfusion offers a promising strategy for mitigating myocardial damage without impairing tissue repair mechanisms. TG100-115 represents a potential therapeutic approach to achieve clinically meaningful cardioprotection in the post-reperfusion phase—a long-standing challenge in the treatment of myocardial infarction.