Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury
Related Experiment Video
Updated: Jul 18, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
John Doukas1, Wolfgang Wrasidlo, Glenn Noronha
1TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA. jdoukas@targegen.com
Abstract:
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.
Insights
Selective inhibition of pro-inflammatory phosphoinositide 3-kinases (PI3Ks) gamma and delta isoforms during reperfusion limits tissue damage and offers cardioprotection in myocardial infarction models.
Area of Science:
- Cardiovascular Research
- Inflammation Biology
- Pharmacology
Background:
- Phosphoinositide 3-kinases (PI3Ks) have dual roles in ischemia/reperfusion injury, with some isoforms promoting cell survival and others exacerbating inflammation.
- Inflammatory PI3K isoforms (gamma and delta) contribute to tissue damage during the reperfusion phase of myocardial infarction.
- Targeting these specific isoforms during reperfusion may mitigate injury.
Purpose of the Study:
- To investigate the therapeutic potential of selectively inhibiting PI3K gamma and delta isoforms during reperfusion to reduce myocardial damage.
- To identify and characterize novel PI3K inhibitors with selectivity for the gamma and delta isoforms.
- To evaluate the efficacy of a selective inhibitor in preclinical models of myocardial infarction.
Main Methods:
- Screening of a novel chemical library to identify PI3K inhibitors.
- Molecular modeling to understand and predict isoform specificity.
- In vitro assessment of inhibitor effects on inflammatory mediators and endothelial cell responses.
- In vivo evaluation of a selective PI3K gamma/delta inhibitor (TG100-115) in animal models of myocardial infarction (MI).
Main Results:
- A selective PI3K gamma/delta inhibitor, TG100-115, was identified.
- TG100-115 potently inhibited edema and inflammation in response to key mediators of MI without affecting endothelial cell repair.
- In animal MI models, TG100-115 demonstrated significant cardioprotection, reducing infarct size and preserving cardiac function.
- Therapeutic benefit was observed even when administered up to 3 hours after reperfusion.
Conclusions:
- Selective inhibition of PI3K gamma and delta isoforms is a promising strategy for limiting reperfusion injury in myocardial infarction.
- TG100-115 offers potent cardioprotection by targeting late-stage inflammatory events post-reperfusion.
- This approach addresses a critical unmet need for effective therapeutic interventions during the accessible post-reperfusion window in clinical settings.
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