PCSK9 regulates the chemokine receptor CCR2 on monocytes
| Autor: | Burkert Pieske, Philipp Hillmeister, Kai Kappert, Heike Meyborg, Taisiya Bezhaeva, Ulrich Kintscher, Philipp Stawowy, Jana Grune |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine medicine.medical_specialty CCR2 Vascular smooth muscle Monocyte chemotaxis Receptors CCR2 p38 mitogen-activated protein kinases Biophysics Inflammation 030204 cardiovascular system & hematology Biochemistry Monocytes Muscle Smooth Vascular Cell Line Rats Sprague-Dawley 03 medical and health sciences Chemokine receptor 0302 clinical medicine Internal medicine medicine Animals Humans Molecular Biology Cells Cultured Chemistry Monocyte Cell Biology Atherosclerosis Angiotensin II Cell biology Toll-Like Receptor 4 Chemotaxis Leukocyte 030104 developmental biology medicine.anatomical_structure Endocrinology lipids (amino acids peptides and proteins) Proprotein Convertase 9 medicine.symptom |
| Zdroj: | Biochemical and Biophysical Research Communications. 485:312-318 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2017.02.085 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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