Promoting plaque stability by gene silencing of monocyte chemotactic protein-3 or overexpression of tissue factor pathway inhibitor in ApoE-/- mice

Chemokines may promote the formation and instability of atherosclerotic plaque, which is the most common cause of acute coronary syndrome. The aim of this study was to clarify the function of monocyte chemotactic protein-3 (MCP-3) in the stability of atherosclerotic plaque, to determine the role of tissue factor pathway inhibitor (TFPI) on the development and stability of atherosclerotic plaques, and to further elucidate the anti-atherosclerotic mechanism of TFPI with the emphasis on chemokine MCP-3. We constructed an adenovirus-mediated shRNA against mouse MCP-3 (Ad-MCP-3-shRNA) and an adenovirus-containing TFPI (Ad-TFPI), and tranferred them in a model of vulnerable plaque in ApoE-/- mice respectively. Here, we reported that MCP-3-shRNA and TFPI could both reduce the plaque area and decrease the content of lipids and macrophages, on the contrary, the fibrous cap thickness and content of collagen and smooth muscle cells were increased. In addition, the expression of MCP-3 and CC chemokine receptor 2 (CCR2) was decreased by TFPI transfer. These data provide the first in vivo evidence that MCP-3 is a major contributor to the unstability of atherosclerotic plaque and TFPI may exert its anti-atherosclerotic effects and promote stabilisation of plaque at least partly through inhibiting MCP-3/CCR2 pathway, which may be a new therapeutic method for atherosclerosis.

Automated summary

The study demonstrates that MCP-3 and TFPI can both reduce the plaque area and decrease lipid and macrophage content, while increasing fibrous cap thickness, collagen, and smooth muscle cell content. TFPI exerts its anti-atherosclerotic effects by inhibiting the MCP-3/CCR2 pathway.