PCSK5 promotes angiogenesis and cardiac repair after myocardial infarction.

Summary

This mechanistic study identifies endothelial PCSK5 as a pro-angiogenic factor that directly cleaves VEGFA, enhancing angiogenesis and cardiac recovery after myocardial infarction. Endothelial Pcsk5 loss impaired repair, while targeted delivery or semaglutide increased vascular density and improved function, suggesting a druggable pathway for ischemic heart disease.

Key Findings

• Plasma PCSK5 levels are elevated in MI patients and associate with cardiac function improvement.
• Endothelial Pcsk5 deficiency impairs angiogenesis and cardiac recovery after MI; endothelial-specific Pcsk5 delivery enhances both.
• PCSK5 directly cleaves VEGFA; Arg158 and Asn164 residues are essential for its pro-angiogenic activity.
• Semaglutide increases vascular density and improves function post-MI partially via endothelial Pcsk5.

Clinical Implications

PCSK5 may serve as a biomarker and therapeutic target to enhance post-MI angiogenesis and functional recovery; GLP-1 receptor agonists might partly act via endothelial Pcsk5, informing drug repurposing or combination strategies.

Limitations

• Predominantly preclinical with male mice; human cohort size and prospective validation not detailed in abstract
• Translational dosing, safety, and off-target effects of modulating PCSK5 remain to be established

Future Directions

Prospective human studies to validate PCSK5 as a biomarker; therapeutic modulation of PCSK5-VEGFA axis (e.g., small molecules/biologics) and evaluation across sexes and comorbidities.