Abstract 11115: Proprotein Convertase Subtilisin/Kexin Type 9 Regulates Migration of Mononuclear Cells
Introduction: Mononuclear cell (MNC) migration is a key element in atherogenesis. LDL-C has been found to facilitate MNC migration via LDL-R related upreguation of CCR2. PCSK9 regulates serum LDL-C via degradation of hepatic LDL-R′s. Recently, PCSK9-expression, lacking in MNCs, has been demonstrated in VSMCs of the vessel wall. Thus, the present study was done to explore the regulation of PCSK9 in VSMCs by inflammation and the impact of VSMC-derived PCSK9 on MNC function.
Methods and Results: PCSK9 mRNA and protein levels were upregulated by the TLR4-ligand lipopolysaccharide (LPS; 100 ng/ml), whereas TGF-β or angiotensin II had no effect. LPS increased PCSK9 mRNA and protein Levels time- and concentration dependently. This was selectively inhibited by TLR4 Blockade with CLI-059 and further downstream with the JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. ELISA-based analyses demonstrated that LPS significantly increased PCSK9 releases from VSMCs, which was further augmented by atorvastatin (10 μM). Incubation of human monocytic THP-1 cells in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels in MNCs, comparable to the effects of recombinant PCSK9. In contrast, stimulation of MNCs with LPS alone did not affect MNC LDL-R levels. However, LDL (100 μg/mL) stimulation of MNCs increased their CCR2 expression, which augmented MNC migration towards MCP-1. This LDL-dependent MNC migration was inhibited by supernatants from LPS-stimulated VSMCs, comparable to the effects of recombinant PCSK9 or a functional LDL-R blocking antibody.
Conclusion: PCSK9 is upregulated in VSMCs by TLR4/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 lessens MNC LDL-R expression, effecting LDL-C/LDL-R-mediated CCR2-expression on MNCs, crucial to MNC motility. In conclusion our data suggests PCSK9 as a key regulator in VSMCs / MNC interaction fundamental to CVD genesis.
Author Disclosures: I.A. Just: None. H. Meyborg: None. S. Molnar: None. D. Urban: None. U. Kintscher: None. E. Fleck: None. P. Stawowy: None.
- © 2014 by American Heart Association, Inc.