Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice.

Abstract

BACKGROUND:

The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X, is expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis.

METHODS:

We generated apolipoprotein E-deficient ( ApoE-/-) mice lacking systemic PAR-2 expression ( PAR-2-/- ApoE-/-). ApoE-/- mice, which lack or express PAR-2 only in bone marrow (BM) cells, were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a Western-type diet by histological analyses, quantitative reverse transcription polymerase chain reaction, and Western blotting. In vitro experiments using BM-derived macrophages were performed to confirm the proinflammatory roles of PAR-2. The association between plasma activated factor X level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention.

RESULTS:

PAR-2-/- ApoE-/- mice showed reduced atherosclerotic lesions in the aortic arch ( P<0.05) along with features of stabilized atherosclerotic plaques, such as less lipid deposition ( P<0.05), collagen loss ( P<0.01), macrophage accumulation ( P<0.05), and inflammatory molecule expression ( P<0.05) compared with ApoE-/- mice. Systemic PAR2 deletion in ApoE-/-mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE-/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that activated factor X or a specific peptide agonist of PAR-2 significantly increased the expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of nuclear factor-κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma activated factor X level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score ( P<0.05) and plaque volume ( P<0.01).

CONCLUSIONS:

PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE-/- mice. This signaling pathway may also participate in atherogenesis in humans.

• Authors: Tomoya Hara, Pham Tran Phuong, Daiju Fukuda, Koji Yamaguchi, Chie Murata, Sachiko Nishimoto, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Issei Imoto, Michio Shimabukuro, Masataka Sata
• Journal: Circulation (Circulation) Vol. 138 Issue 16 Pg. 1706-1719 (10 16 2018) ISSN: 1524-4539 [Electronic] United States
• PMID: 29700120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• F2RL1 protein, human
• F2rl1 protein, mouse
• Inflammation Mediators
• Lipids
• Receptor, PAR-2
• Receptors, G-Protein-Coupled
• Factor Xa

Topics

• Aged
• Animals
• Aorta, Thoracic (metabolism, pathology)
• Aortitis (genetics, metabolism, pathology, prevention & control)
• Atherosclerosis (genetics, metabolism, pathology, prevention & control)
• Cells, Cultured
• Coronary Artery Disease (metabolism, pathology)
• Diet, Western
• Disease Models, Animal
• Factor Xa (metabolism)
• Female
• Humans
• Inflammation Mediators (metabolism)
• Lipids (blood)
• Macrophage Activation
• Macrophages (metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Plaque, Atherosclerotic
• Receptor, PAR-2 (deficiency, genetics, metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Signal Transduction