sema-HUVEC

Secreted proteins are crucial for angiogenesis and cardiac repair following myocardial infarction (MI). Although PCSK5 (proprotein convertase subtilisin/kexin 5) is essential for heart development, its role in MI is unexplored. We found that the plasma levels of PCSK5 were elevated in MI patients and exhibited potential in predicting cardiac function improvement. PCSK5 expression was upregulated in the cardiac endothelial cells (ECs) of MI patients. Pcsk5 deficiency in ECs impaired angiogenesis and cardiac recovery post-MI, and delayed tissue repair following hindlimb ischemic injury in male mice. In contrast, the endothelial-specific Pcsk5 delivery enhanced angiogenesis and cardiac function post-MI. Single-nucleus RNA sequencing showed that PCSK5 increased capillary endothelial cells in the ischemic mouse hearts. PCSK5 was found to directly cleave vascular endothelial growth factor A (VEGFA), activating its signaling and promoting angiogenic activity. The residues Arg158 and Asn164 of PCSK5 were crucial for its function. In MI patients, PCSK5 plasma levels positively correlated with VEGFA and glucagon-like peptide-1. Semaglutide enhanced PCSK5 expression through the transcription factor ETS1, enhancing angiogenic activity in ECs. It also increased vascular densities and cardiac function post-MI, partially through EC-derived Pcsk5 in male mice. This study identified PCSK5 as a pro-angiogenic factor secreted by ECs and suggested its potential as a therapeutic target for ischemic diseases.

分泌蛋白（Secreted proteins）对于心肌梗死（myocardial infarction, MI）后的血管生成与心脏修复至关重要。尽管前蛋白转化酶枯草溶菌素/kexin 5型（proprotein convertase subtilisin/kexin 5, PCSK5）对心脏发育不可或缺，但其在心肌梗死中的作用尚未被探索。我们发现，心肌梗死患者血浆中的PCSK5水平升高，且具备预测心脏功能改善的潜在价值。心肌梗死患者的心脏内皮细胞（cardiac endothelial cells, ECs）中PCSK5的表达上调。内皮细胞特异性缺失Pcsk5会损害雄性小鼠心肌梗死后的血管生成与心脏恢复，并延缓其后肢缺血损伤后的组织修复过程。与之相反，内皮细胞特异性递送Pcsk5可增强心肌梗死后的血管生成与心脏功能。单细胞核RNA测序（single-nucleus RNA sequencing）结果显示，PCSK5可增加缺血小鼠心脏中的毛细血管内皮细胞数量。研究发现PCSK5可直接切割血管内皮生长因子A（vascular endothelial growth factor A, VEGFA），激活其信号通路并促进血管生成活性。PCSK5的精氨酸158（Arg158）与天冬酰胺164（Asn164）残基对其功能至关重要。在心肌梗死患者中，血浆PCSK5水平与VEGFA及胰高血糖素样肽-1（glucagon-like peptide-1）呈正相关。司美格鲁肽（Semaglutide）可通过转录因子ETS1上调PCSK5的表达，增强内皮细胞的血管生成活性；同时还可提高雄性小鼠心肌梗死后的血管密度与心脏功能，这一作用部分依赖于内皮细胞来源的Pcsk5。本研究证实PCSK5是一种由内皮细胞分泌的促血管生成因子，并提示其有望成为缺血性疾病的治疗靶点。