title: Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury.
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.
authors.affiliation: TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA. jdoukas@targegen.com
authors.forename: John
authors.initials: J
authors.lastname: Doukas
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Glenn
authors.initials: G
authors.lastname: Noronha
authors.forename: Elena
authors.initials: E
authors.lastname: Dneprovskaia
authors.forename: Richard
authors.initials: R
authors.lastname: Fine
authors.forename: Sara
authors.initials: S
authors.lastname: Weis
authors.forename: John
authors.initials: J
authors.lastname: Hood
authors.forename: Anthony
authors.initials: A
authors.lastname: Demaria
authors.forename: Richard
authors.initials: R
authors.lastname: Soll
authors.forename: David
authors.initials: D
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008958:Models, Molecular; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D013552:Swine
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits