Tumor Necrosis Factor Receptor-Associated Factor 5 Promotes Arterial Neointima Formation through Smooth Muscle Cell Proliferation.

Abstract

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins of the TNF/interleukin (IL)-1/Toll-like receptor superfamily. Ligands of this family such as TNFα, CD40L, and IL-1β promote chronic inflammatory processes such as atherosclerosis and restenosis, the latter being a common adverse reaction after vascular interventions. We previously reported overexpression of TRAF5 in murine and human atheromata and TRAF5-dependent proinflammatory functions in vitro. However, the role of TRAF5 in restenosis remains unsettled. To evaluate whether TRAF5 affects neointima formation, TRAF5-/-LDLR-/- and TRAF5+/+LDLR-/- mice consuming a high cholesterol diet (HCD) received wire-induced injury of the carotid artery. After 28 days, TRAF5-deficient mice showed a 45% decrease in neointimal area formation compared with TRAF5-compentent mice. Furthermore, neointimal vascular smooth muscle cells (vSMC) and macrophages decreased whereas collagen increased in TRAF5-deficient mice. Mechanistically, the latter expressed lower transcript levels of the matrix metalloproteinases 2 and 9, both instrumental in extracellular matrix degradation and vSMC mobilization. Additionally, TRAF5-specific siRNA interference rendered murine vSMC less proliferative upon CD40L stimulation. In accordance with these findings, fewer vSMC isolated from TRAF5-deficient aortas were in a proliferative state as assessed by Ki67 and cyclin B1 expression. In conclusion, TRAF5 deficiency mitigates neointima formation in mice, likely through a TRAF5-dependent decrease in vSMC proliferation.

• Authors: Florian Willecke, Benjamin Rupprecht, Mark Colin Gissler, Katharina Pfeiffer, Nathaly Anto-Michel, Peter Stachon, Dennis Wolf, Ingo Hilgendorf, Natalie Hoppe, Christoph Bode, Andreas Zirlik
• Journal: Journal of vascular research (J Vasc Res) Vol. 56 Issue 6 Pg. 308-319 ( 2019) ISSN: 1423-0135 [Electronic] Switzerland
• PMID: 31437850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 S. Karger AG, Basel.

Chemical References

• CD40 Antigens
• Cholesterol, Dietary
• Receptors, LDL
• TNF Receptor-Associated Factor 5
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• CD40 Antigens (metabolism)
• Carotid Arteries (metabolism, pathology)
• Carotid Artery Diseases (genetics, metabolism, pathology)
• Cell Proliferation
• Cholesterol, Dietary
• Disease Models, Animal
• Macrophages (metabolism, pathology)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (metabolism, pathology)
• Myocytes, Smooth Muscle (metabolism, pathology)
• Neointima
• Plaque, Atherosclerotic
• Receptors, LDL (genetics, metabolism)
• Signal Transduction
• TNF Receptor-Associated Factor 5 (deficiency, genetics, metabolism)