Endothelial soluble APP/APLP2 promote heart repair through KIT-mediated angiogenesis.

Summary

This mechanistic study demonstrates that endothelial APP/APLP2 are processed under hypoxia to soluble APPsα/APLP2sα, which positively allosterically modulate endothelial KIT to drive post-MI angiogenesis. Endothelial deletion worsened neovascularization, heart failure, and mortality, while endothelial APPsα expression rescued the phenotype.

Key Findings

• Hypoxia upregulates endothelial α-secretases, generating soluble APPsα/APLP2sα via nonamyloidogenic processing.
• Endothelial APP/APLP2 loss reduces neovascularization and increases post-MI heart failure and mortality; endothelial APPsα expression rescues these deficits.
• APPsα/APLP2sα act as positive allosteric modulators of endothelial KIT to promote post-ischemic angiogenesis.

Clinical Implications

Therapeutic strategies enhancing APPsα/APLP2sα signaling or KIT positive allosteric modulation could augment post-MI revascularization. Caution may be warranted when targeting amyloid pathways to avoid compromising cardiac repair.

Limitations

• Preclinical models without human clinical validation
• Potential off-target effects and safety of modulating APP/KIT signaling not addressed

Future Directions

Test APPsα/KIT-targeted interventions in large-animal MI models and evaluate safety-efficacy in early-phase clinical studies; explore interactions with anti-amyloid therapies.