CD137-CD137L interaction regulates atherosclerosis via cyclophilin A in apolipoprotein E-deficient mice

• Published in: PloS one Vol. 9; no. 2; p. e88563
• Main Authors: Li, Yuefeng, Yan, Jinchuan, Wu, Chao, Wang, Zhongqun, Yuan, Wei, Wang, Dongqing
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-02-2014; Public Library of Science (PLoS)
• Subjects: 4-1BB Ligand - metabolism; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - deficiency; Apolipoproteins E - metabolism; Arteries; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Cardiology; Carotid arteries; Carotid artery; CD137 antigen; Chemokines; Coronary heart disease; Coronary vessels; Cyclophilin A - metabolism; Cytokines; Disease Progression; High fat diet; Inflammation; Laboratories; Ligands; Male; Matrix metalloproteinases; Medical research; Medicine; Mice; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Protein Binding; Restoration; Signal Transduction; Smooth muscle; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; Tumor necrosis factor-TNF; Viral genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0088563

Our previous studies showed that increased levels of cyclophilin A (CyPA) may be a valuable marker for predicting the severity of acute coronary syndromes and that interruption of CD137-CD137L interactions diminished the formation and progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Here, we sought to determine whether the proinflammatory factor CyPA is involved in atherosclerosis regulated by CD137-CD137L interactions.
A constrictive collar was placed around the right carotid arteries of ApoE-/- mice that were fed a high-fat diet to induce atherosclerotic plaque formation. After that, the mice were intraperitoneally injected with anti-CD137 or anti-CD137L in the presence or absence of the recombinant lentiviral vectors LVTHM-CyPA or pGC-FU-CyPA, respectively. Interestingly, activation of CD137-CD137L was negatively correlated with CyPA expression in vivo and in vitro. Stimulating CD137-CD137L interaction significantly increased CyPA, which was concurrent with the upregulation of proinflammatory cytokines, chemokines and matrix metalloproteinases and resulted in the promotion of atherosclerosis in ApoE-/- mice. Silencing CyPA could eliminate these effects, and restoration of CyPA effectively and consistently attenuated the atherosclerotic suppression phenotypes elicited by the blockade of CD137-CD137L.
These observations suggest that CD137-CD137L interactions mediated via regulation of CyPA contribute to the progression of atherosclerosis.