FSP-1 silencing in bone marrow cells suppresses neointima formation in vein graft.

Abstract

RATIONALE:

Fibroblast-specific protein 1 (FSP-1) plays multiple roles in promoting cell proliferation and motility. Increased FSP-1 expression in smooth muscle cells (SMCs) has been associated with their enhanced proliferation.

OBJECTIVE:

To study how FSP-1 contributes to neointima formation of vein grafts.

METHODS:

Arteriovenous grafts were created in wild-type or FSP-1-GFP mice (green fluorescent protein expression regulated by FSP-1 promoter). The effects of FSP-1 on bone marrow (BM) cell migration and on SMC proliferation were studied in vivo and in vitro.

RESULTS:

On creation of a vein graft, there was rapid deposition of platelets on the denuded surface leading to secretion of the chemokine stromal cell-derived factor-1α (SDF-1α). This was followed by recruitment of BM-derived cells expressing the SDF-1α receptor CXCR4; homing of FSP-1-positive cells was found to be dependent on platelet-derived SDF-1α. FSP-1 was expressed in 8% of the BM cells, and 20% of these express CD45; 85% of FSP-1-positive cells express CD11b. We found that the FSP-1-positive cells migrated into the vein graft in a Rac-1-dependent fashion. FSP-1 expression was also found to stimulate proliferation of SMCs through a MEK5-ERK5 signaling pathway that can be suppressed by a dominant-negative Rac1. Consequently, knocking down FSP-1 expression in BM cells prevented neointimal formation.

CONCLUSIONS:

BM-derived FSP-1(+) cells enhance neointima formation through an increase in transendothelial invasion with stimulation of SMC proliferation. The Rac1 and ERK5 signaling cascade mediate FSP-1-induced responses in SMCs and BM cells. This novel pathophysiology suggests a new therapeutic target, FSP-1, for preventing the development of neointima in vein grafts.

• Authors: Jizhong Cheng, Yun Wang, Anlin Liang, Lixin Jia, Jie Du
• Journal: Circulation research (Circ Res) Vol. 110 Issue 2 Pg. 230-40 (Jan 20 2012) ISSN: 1524-4571 [Electronic] United States
• PMID: 22116816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Cxcl12 protein, mouse
• Inflammation Mediators
• Neuropeptides
• Rac1 protein, mouse
• Recombinant Fusion Proteins
• S100 Calcium-Binding Protein A4
• S100 Proteins
• S100a4 protein, mouse
• Green Fluorescent Proteins
• Mitogen-Activated Protein Kinase 7
• MAP Kinase Kinase 5
• rac GTP-Binding Proteins
• rac1 GTP-Binding Protein

Topics

• Animals
• Blood Platelets (metabolism)
• Bone Marrow Cells (metabolism)
• Bone Marrow Transplantation
• Cell Proliferation
• Cells, Cultured
• Chemokine CXCL12 (metabolism)
• Coculture Techniques
• Genetic Therapy
• Green Fluorescent Proteins (genetics, metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Hyperplasia
• Inflammation Mediators (metabolism)
• MAP Kinase Kinase 5 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 7 (metabolism)
• Neuropeptides (metabolism)
• Promoter Regions, Genetic
• RNA Interference
• Recombinant Fusion Proteins (metabolism)
• S100 Calcium-Binding Protein A4
• S100 Proteins (genetics, metabolism)
• Signal Transduction
• Transendothelial and Transepithelial Migration
• Tunica Intima (metabolism, pathology, transplantation)
• Vascular Grafting
• Vena Cava, Inferior (metabolism, pathology, transplantation)
• rac GTP-Binding Proteins (metabolism)
• rac1 GTP-Binding Protein