Nucleotide-binding oligomerization domain protein 2 deficiency enhances neointimal formation in response to vascular injury.

Abstract

OBJECTIVE:

Nucleotide-binding oligomerization domain protein 2 (NOD2) stimulates diverse inflammatory responses resulting in differential cellular phenotypes. To identify the role of NOD2 in vascular arterial obstructive diseases, we investigated the expression and pathophysiological role of NOD2 in a vascular injury model of neointimal hyperplasia.

METHODS AND RESULTS:

We first analyzed for neointimal hyperplasia following femoral artery injury in NOD2(+/+) and NOD2(-/-) mice. NOD2(-/-) mice showed a 2.86-fold increase in neointimal formation that was mainly composed of smooth muscle (SM) α-actin positive cells. NOD2 was expressed in vascular smooth muscle cells (VSMCs) and NOD2(-/-) VSMCs showed increased cell proliferation in response to mitogenic stimuli, platelet-derived growth factor-BB (PDGF-BB), or fetal bovine serum, compared with NOD2(+/+) VSMCs. Furthermore, NOD2 deficiency markedly promoted VSMCs migration in response to PDGF-BB, and this increased cell migration was attenuated by a phosphatidylinositol 3-kinase inhibitor. However, protein kinase C and c-Jun N-terminal kinase inhibitors exerted negligible effects. Moreover, muramyl dipeptide-stimulated NOD2 prevented PDGF-BB-induced VSMCs migration.

CONCLUSION:

Functional NOD2 was found to be expressed in VSMCs, and NOD2 deficiency promoted VSMCs proliferation, migration, and neointimal formation after vascular injury. These results provide evidence for the involvement of NOD2 in vascular homeostasis and tissue injury, serving as a potential molecular target in the modulation of arteriosclerotic vascular disease.

• Authors: Min-Young Kwon, Xiaoli Liu, Seon-Jin Lee, Young-Ho Kang, Augustine M K Choi, Ki-Up Lee, Mark A Perrella, Su Wol Chung
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 11 Pg. 2441-7 (Nov 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21903945 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Nod2 Signaling Adaptor Protein
• Nod2 protein, mouse
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• RNA, Small Interfering
• Becaplermin

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Animals
• Aorta (metabolism, pathology)
• Becaplermin
• Cell Movement (drug effects, physiology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Femoral Artery (injuries, metabolism, pathology)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• Muscle, Smooth, Vascular (injuries, metabolism, pathology)
• Neointima (metabolism, pathology, physiopathology)
• Nod2 Signaling Adaptor Protein (deficiency, genetics, metabolism)
• Platelet-Derived Growth Factor (pharmacology)
• Proto-Oncogene Proteins c-sis
• RNA, Small Interfering (pharmacology)