Hemodynamic Shear Stress via ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and Along the Mouse Aorta

Aims: To investigate a possible link between hemodynamic shear stress, reactive oxygen species (ROS) generation, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Results: Using a parallel-plate flow chamber, we observed that PCSK9 expression in vascular smooth muscle cells (SMCs) and endothelial cells (ECs) reached maximal value at low shear stress (3-6 dynes/cm(2)), and then began to decline with an increase in shear stress. PCSK9 expression increased when cells were treated with lipopolysaccharide. PCSK9 expression was always greater in SMCs than in ECs. ROS generation followed the same pattern as PCSK9 expression. Aortic branching and aorta-iliac bifurcation regions of mouse aorta that express low shear stress were also found to have greater PCSK9 expression (vs. other regions). To determine a relationship between ROS and PCSK9 expression, ECs and SMCs were treated with ROS inhibitors diphenylene-iodonium chloride and apocynin, and both markedly reduced PCSK9 expression. Relationship between PCSK9 and ROS was further studied in p47(phox) and gp91(phox) knockout mice; both mice strains revealed low PCSK9 levels in serum and mRNA levels in aorta-iliac bifurcation regions (vs. wild-type mice). Other studies showed that ROS and NF-kappa B activation plays a bridging role in PCSK9 expression via lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Innovation: Low shear stress induces PCSK9 expression, which is mediated by NADPH oxidase-dependent ROS production. Conclusions: This study provides evidence that low shear stress enhances PCSK9 expression in concert with ROS generation in vascular ECs and SMCs. ROS seem to regulate PCSK9 expression. We propose that PCSK9-ROS interaction may be important in the development of atherosclerosis in arterial channels with low shear stress. Antioxid. Redox Signal. 22, 760-771.