Fig. 6. Small-molecule TNNI3K inhibitors reduce infarct size and protect the heart after I/R.

WT C57BL/6 mice were treated at reperfusion with vehicle [20% aqueous Cavitron + 5% dimethyl sulfoxide (DMSO)] or two small-molecule TNNI3K inhibitors. (A) Chemical structures of small-molecule inhibitors. (B) Representative LV sections from n = 7 animals per group, 24 hours after I/R. Dashed lines demarcate infarcted tissue. (C and D) Infarct sizes and AARs 24 hours after I/R. (E) Representative confocal micrographs from n = 5 animals per group of DHE-stained LV tissue. Quantification of superoxide levels (as fold change in mean DHE intensity versus vehicle treatment at 30 min after I/R) is shown below the representative images. (F) Immunoblots for p38 MAPK phosphorylation status in ischemic LV lysates 3 hours after I/R. GAPDH served as a loading control. Quantification is shown below. (G) Mitochondrial membrane potential (Δψ_m) at baseline or in response to four pulses of 10 μM Ca²⁺ in WT C57BL/6 mouse myocytes subjected to hypoxia (1% O₂) for 2 hours, followed by reoxygenation for 30 min. Cells were treated with GSK854, immediately before hypoxia (Pre) or upon reoxygenation (Post). (H and I) Quantification of Δψ_m (H) and bath [Ca²⁺] after CCCP (I), in response to four pulses of 10 μM Ca²⁺, from n = 3 animals per group. All data are shown as means ± SEM. *P < 0.05, **P < 0.01 as determined by two-tailed Student’s t test (F) or one-way ANOVA followed by Tukey’s post hoc test (all others).