Fig. 8: The HIP-55 signalosome-dependent ferroptosis pathway reduces myocardial infarction injury.
From: Adaptor protein HIP-55-mediated signalosome protects against ferroptosis in myocardial infarction
A Genotyping of wildtype, HIP-55WTTg and HIP-55AATg mice. B Western blots analysis of cardiac proteins from WT, HIP-55WTTg, and HIP-55AATg mice displaying overexpression of HIP-55 in the transgenic hearts. C HIP-55 inhibited MI-induced JNK activation in a S269/T291-dependent manner. Western blots analysis of JNK phosphorylation in the heart tissues of WT, HIP-55WTTg and HIP-55AATg mice after MI. n = 5. D HIP-55 inhibited MI-induced cardiomyocyte ferroptosis relies on its S269/T291 phosphorylation state. Representative immunoblots and statistical data of GPX4 expression in heart tissue from WT, HIP-55WTTg, and HIP-55AATg mice after MI. n = 6. E Relative expression of MDA in heart tissue from WT, HIP-55WTTg and HIP-55AATg mice after MI. n = 7. F Relative expression of GSH in heart tissue from WT, HIP-55WTTg and HIP-55AATg mice after MI. n = 7. G Relative activity of SOD in heart tissue from WT, HIP-55WTTg and HIP-55AATg mice after MI. n = 7. H HIP-55 suppressed myocardial infarction size depends on its S269/T291 phosphorylation. Representative Alcian blue-TTC staining and statistical data for area at risk and infarct size in heart tissue from WT, HIP-55WTTg, and HIP-55AATg mice post-MI. WT, n = 9; HIP-55WTTg, n = 11; HIP-55AATg, n = 9. I HIP-55 suppressed MI-induced cardiac contractile dysfunction in an S269/T291-dependent manner. Representative M-mode echocardiographic photographs (left) and cardiac contractile function (right) quantified by echocardiographic analysis of ejection fraction (EF) and fractional shortening (FS) in WT, HIP-55WTTg, and HIP-55AATg mice after MI. n = 5–7. J HIP-55 alleviated cardiac hypertrophy after MI depends on its S269/T291 phosphorylation. The ratio of heart weight to tibial length (HW/TL) in WT, HIP-55WTTg and HIP-55AATg mice. n = 6–7. *P < 0.05, **P < 0.01. All error bars represent mean ± SEM. K The schematic diagram of HIP-55-dependent signalosome determines cardiomyocyte fate. HIP-55 functions as the central hub to assemble AKT, 14-3-3τ and MAP4K1 to form a signalosome, where AKT phosphorylates HIP-55 at its S269/T291 sites and HIP-55 then rewires AKT signaling to negatively regulate the MAP4K1 cell death pathway against ferroptosis and MI injury in a site-specific manner.
