Jana Grune1, Heike Meyborg2, Taisiya Bezhaeva3, Kai Kappert4, Philipp Hillmeister5, Ulrich Kintscher6, Burkert Pieske7, Philipp Stawowy8. 1. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany; Institute of Pharmacology and Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany; DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany. 2. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany. 3. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany; Master's Program Molecular Medicine, Charité-UniversitätsmedizinBerlin, Germany. 4. DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Germany. 5. Department for Internal Medicine I, Brandenburg Clinic, Brandenburg Medical School, Germany; Center for Cardiovascular Research, Richard-Thoma-Laboratories, Charité-Universitätsmedizin Berlin, Germany. 6. Institute of Pharmacology and Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany; DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany. 7. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany; DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany; Department of Cardiology / Virchow-Campus, Charité-Universitätsmedizin Berlin, Germany. 8. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany. Electronic address: stawowy@dhzb.de.
Abstract
Monocyte migration is a key element in atherosclerosis. LDL-C facilitates monocyte migration via induction of CCR2. PCSK9 regulates cell surface expression of the LDL-R and is expressed in vascular smooth muscle cells (VSMCs). The present study was done to investigate the regulation of PCSK9 in VSMCs and its impact on monocyte function. METHODS AND RESULTS: PCSK9 mRNA and protein levels were upregulated in VSMCs by the TLR-4 ligand LPS, whereas TGF-β or angiotensin II had no effect. Induction of PCSK9 was selectively inhibited by TLR-4 blockade and further downstream by the SAPK/JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. Incubation of monocytes in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels on monocytes, comparable to the effects of recombinant PCSK9. LDL-C increased monocyte CCR2 expression, which augmented monocyte migration towards MCP-1. This LDL-C dependent monocyte chemotaxis was inhibited by supernatants from LPS-stimulated VSMCs, similar to recombinant PCSK9 and a specific LDL-R blocking antibody. CONCLUSION: PCSK9 is regulated in VSMCs by TLR-4 - SAPK/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 reduces monocyte LDL-R expression, affecting LDL-C/LDL-R-mediated CCR2-expression on monocytes, which is crucial to cell motility and atherogenesis.
Monocyte migration is a key element in atherosclerosis. LDL-C facilitates monocyte migration via induction of CCR2. PCSK9 regulates cell surface expression of the LDL-R and is expressed in vascular smooth muscle cells (VSMCs). The present study was done to investigate the regulation of PCSK9 in VSMCs and its impact on monocyte function. METHODS AND RESULTS:PCSK9 mRNA and protein levels were upregulated in VSMCs by the TLR-4 ligand LPS, whereas TGF-β or angiotensin II had no effect. Induction of PCSK9 was selectively inhibited by TLR-4 blockade and further downstream by the SAPK/JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. Incubation of monocytes in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels on monocytes, comparable to the effects of recombinant PCSK9. LDL-C increased monocyte CCR2 expression, which augmented monocyte migration towards MCP-1. This LDL-C dependent monocyte chemotaxis was inhibited by supernatants from LPS-stimulated VSMCs, similar to recombinant PCSK9 and a specific LDL-R blocking antibody. CONCLUSION:PCSK9 is regulated in VSMCs by TLR-4 - SAPK/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 reduces monocyte LDL-R expression, affecting LDL-C/LDL-R-mediated CCR2-expression on monocytes, which is crucial to cell motility and atherogenesis.
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