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. 2023 Jun 15;12(12):e022352. doi: 10.1161/JAHA.122.022352

Figure 1. Risk pathway, PI3Kα, and ischemia–reperfusion injury.

Figure 1

A, Schematic of the risk pathway, a possible link between PI3Kα and mPTP formation, and necroptosis pathways. B, Deletion of p110α after 2 days of tamoxifen treatment (40 mg/kg) in p110α‐Mer compared with non‐Mer (WT) littermate controls (n=4). C, RPP in response to 30‐minute ischemia in WT, constituent PI3Kα‐deficient (p110α‐DN), and inducible PI3Kα‐deficient (p110α‐Mer) excised hearts (n=6–8). D, Rate pressure product (RPP) in response to 60‐minute ischemia in WT (open squares), constituent PI3Kα‐deficient (p110α‐DN, open circles), and inducible PI3Kα‐deficient (p110α‐Mer, open rhombi) excised hearts (n=5–6). Inset: pictures of WT (left) and p110α‐DN (right) hearts. E, Effect of MEK162 on RPP in response to 30‐minute ischemia in WT and constituent PI3Kα‐deficient (p110α‐DN) excised hearts (n=4–6). IR30, 30‐minute ischemia followed by reperfusion. F, Effect of MK2206 on RPP in response to 30‐minute ischemia in WT and constituent PI3Kα‐deficient (p110α‐DN) excised hearts (n=4–6). G, Phosphorylation levels of ERK1/2 in cell lysates from WT, WT+MEK162, and p110α‐DN+MEK162 hearts; phosphorylation levels of pAkt‐S473 in cell lysates from WT, WT+MK2206, and p110α‐DN+MK2206 hearts; phosphorylation levels of pAkt‐T309 in cell lysates from WT, WT+MK2206, and p110α‐DN+MK2206 hearts. H, Infarcted areas as % of total area for WT (blue squares) and p110α‐DN (red circles). I, Representative images of heart sections for WT and p110α‐DN hearts. Data are presented as mean±SEM; statistical significance is calculated using Student t test in (B, H) and 1‐way ANOVA in (E through G); **P<0.05 vs WT after 30‐minute reperfusion (WT IR30) no MEK162 (E), **P<0.05 vs WT after 30‐minute reperfusion (WT IR30) no MK2206 (F), *P<0.05 vs WT (B, G, H). Akt indicates protein kinase B; Ca2+mito, mitochondrial Ca2+; CaMKII, calmodulin‐dependent protein kinase II; ERK1/2, a mitogen‐activated protein kinase encoded by the MAPK3 and MAPK1; INa,L, late Na+ current; MEK1/2, mitogen‐activated protein kinase 1/2; MEK162, MEK1/2 inhibitor; MK2206, Akt inhibitor; mPTP, mitochondrial permeability transition pore; Na+i, intracellular sodium; P.S., protein stain; p110α, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K), catalytic subunit α; PI3Kα, phosphoinositide 3‐kinase α; RIP, phospho‐receptor‐interacting serine/threonine‐protein kinase; and RPP, rate pressure product.