PCSK5 promotes angiogenesis and cardiac repair after myocardial infarction by cleaving VEGFA; Semaglutide acts partially via EC-derived PCSK5.

Myocardial infarction (MI) leads to significant cardiac damage and impaired function due to ischemia. Current therapies often fall short in promoting effective cardiac repair and angiogenesis, which are crucial for restoring blood flow and tissue viability. Proprotein convertase subtilisin/kexin 5 (PCSK5), distinct from the more widely known PCSK9 involved in lipid metabolism, is known to be essential for heart development. However, its specific role in adult cardiac repair post-MI, particularly its angiogenic potential, has remained largely unexplored, representing a critical gap in understanding mechanisms for ischemic disease treatment.

Researchers investigated PCSK5's role in myocardial infarction (MI) using human patient samples and male mouse models. They analyzed plasma PCSK5 levels in MI patients and its expression in cardiac endothelial cells (ECs). To assess function, they utilized Pcsk5 deficient ECs and an endothelial-specific Pcsk5 delivery system in mice post-MI and following hindlimb ischemic injury. The study also explored the mechanistic interaction of PCSK5 with VEGFA and examined the effects of Semaglutide on vascular densities and cardiac function post-MI, linking its action to EC-derived Pcsk5.

Plasma PCSK5 levels were elevated in MI patients and showed potential for predicting cardiac function improvement. PCSK5 expression was significantly upregulated in cardiac endothelial cells (ECs) of MI patients. Mechanistically, PCSK5 directly cleaved VEGFA, thereby activating its signaling pathway and promoting angiogenic activity. The specific residues Arg158 and Asn164 of PCSK5 were identified as crucial for this function. Furthermore, Semaglutide increased vascular densities and cardiac function post-MI, with this effect partially mediated through EC-derived Pcsk5 in male mice.

Pcsk5 deficiency in ECs impaired angiogenesis and cardiac recovery post-MI, and delayed tissue repair following hindlimb ischemic injury in male mice. Conversely, endothelial-specific Pcsk5 delivery enhanced angiogenesis and cardiac function post-MI.