Departments of Biochemistry and Molecular Biology and Physiology and Pharmacology (Y. Guo, Z.T., B.Y., H.Y., Y. Gui, X.-L. Zheng).
Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (Y. Guo, S.T., S.Z.).
Arterioscler Thromb Vasc Biol. 2022 Jan;42(1):67-86. doi: 10.1161/ATVBAHA.121.316902. Epub 2021 Nov 23.
PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the "shoulder" regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin.
Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.
PCSK9（脯氨酸羧肽酶/枯草杆菌蛋白酶 Kexin 9 型）通过肝脏中的 PCSK9-LDLR（低密度脂蛋白受体）轴在胆固醇代谢中发挥关键作用；然而，有证据表明，PCSK9 通过独立于其 LDL 胆固醇调节的机制直接促成各种疾病的发病机制。本研究的目的是确定 PCSK9 如何直接作用于血管平滑肌细胞（SMC），导致退行性血管疾病。
我们首先研究了 PCSK9 对培养的人主动脉平滑肌细胞的影响。PCSK9 的过表达下调了 ApoER2（载脂蛋白 E 受体 2）的表达，ApoER2 是 PCSK9 的已知靶点。用可溶性重组人 ApoER2 或 DNA 合成抑制剂羟基脲处理，可抑制 PCSK9 诱导的人平滑肌细胞的多倍体化和其他细胞反应。用针对 ApoER2 的抗体处理可产生与 PCSK9 过表达观察到的相似效果。在小鼠颈动脉中，SMC 特异性诱导敲除 加速了动脉内膜的新生，减少了与年龄相关的动脉僵硬。PCSK9 在人动脉粥样硬化病变的 SMC 中表达，并在易损性动脉粥样硬化斑块的“肩部”区域丰富表达。PCSK9 也在腹主动脉瘤的 SMC 中表达，与平滑肌α-肌动蛋白的表达呈负相关。
我们的研究结果表明，PCSK9 抑制增殖并诱导多倍体化、衰老和凋亡，这可能与各种退行性血管疾病有关。
