Vascular endothelial cell (EC) dysfunction is a pathological mediator of he development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol. Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increased PCSK9 mRNA expression and PCSK9 protein levels in isolated human aortic ECs, which were accompanied by reduced total and phosphorylated endothelial nitric oxide synthase (eNOS) protein levels and NO bioavailability. Finally, genetic PCSK9 reduction utilizing a PCSK9 specific siRNA in human aortic ECs resulted in the rescue of phosphorylated eNOS protein levels and NO bioavailability. Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation of PCSK9 expression utilizing a small interfering RNA against PCSK9 rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease.

中文翻译：

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前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型将炎症与血管内皮细胞功能障碍联系起来

血管内皮细胞（EC）功能障碍是动脉粥样硬化疾病的发展，进展和临床表现的病理介质。炎症与EC功能障碍有关，但负责任的机制尚不清楚。有大量证据表明，在促炎状态下血清前蛋白转化酶枯草杆菌蛋白酶/ kexin型9（PCSK9）升高，并且在控制了包括低密度脂蛋白（LDL）胆固醇在内的传统危险因素后，PCSK9水平升高与不良心血管预后相关。在这里，我们调查PCSK9作为一氧化氮（NO）生物利用度评估的炎症与血管EC功能障碍之间的新型联系。促炎细胞因子肿瘤坏死因子α（TNF-α），在孤立的人主动脉EC中增加PCSK9 mRNA表达和PCSK9蛋白水平，并伴有总和磷酸化内皮一氧化氮合酶（eNOS）蛋白水平降低和NO生物利用度降低。最后，在人主动脉EC中利用PCSK9特异性siRNA进行遗传PCSK9还原，可以挽救磷酸化的eNOS蛋白水平和NO的生物利用度。我们的结果表明，PCSK9在暴露于促炎性刺激的人主动脉EC中增加，并且这种增加与EC功能障碍有关。利用针对PCSK9的小干扰RNA沉默TNFα介导的PCSK9表达增强，挽救了炎症诱导的EC功能障碍。这些结果表明PCSK9是炎症与EC功能障碍之间的因果关系，