PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a key role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver. However, there is evidence that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL cholesterol regulation. Here, researchers show that overexpression of PCSK9 downregulates 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 smooth muscle cells (SMCs). Treatment with anti-ApoER2 antibodies produced effects similar to those produced by PCSK9 overexpression. Inducible, SMC-specific knockout of Pcsk9 accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 is expressed in smooth muscle cells of human atherosclerotic lesions and is enriched in the “shoulder” region of vulnerable atherosclerotic plaques. PCSK9 is also expressed in smooth muscle cells of abdominal aortic aneurysms and negatively correlates with the expression of smooth muscle α-actin. These findings suggest that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be associated with various degenerative vascular diseases.
PCSK9 has been reported to induce dedifferentiation and proliferation of mouse vascular smooth muscle cells. In contrast, the results here showed that overexpression of PCSK9 by adenovirus (as shown by WB assay) (Figure 1A) significantly inhibited the growth of cultured human aortic smooth muscle cells as early as 2 days after transduction compared with smooth muscle cells transduced with Null adenovirus (Ad-Null) (Figure 1B). LSC analysis showed that 24-hour overexpression of PCSK9 significantly reduced the number of BrdU-positive cells (Figures 1C and 1D) but increased BrdU-positive cells in the ≥4 N DNA region (Figures 1C and 1E) compared with smooth muscle cells transduced with control Ad-Null. LSC relocalization of cells with >4 N DNA confirmed their polyploidy (Figure 1C).
Figure 1. PCSK9 inhibits the growth of human aortic smooth muscle cells (SMCs). (Guo Y, et al., 2022)
Customer Reviews
Perfect Control Vector!
Used as a negative control in multiple assays—consistent and contamination-free. A must-have for adenovirus-based studies!
Write a Review