Functions of cyclophilin A in atherosclerosis

Abstract

Cyclophilin A (CypA) is a ubiquitously distributed protein present both in intracellular and extracellular spaces. In atherosclerosis, various cells, including endothelial cells, monocytes, vascular smooth muscle cells and platelets, secrete CypA in response to excessive levels of reactive oxygen species. Atherosclerosis, a complicated disease, is the result of the interplay of different risk factors. Researchers have found that CypA links many risk factors, including hyperlipidemia, hypertension and diabetes, to atherosclerosis that develop into a vicious cycle. Furthermore, most studies have shown that secreted CypA participates in the developmental process of atherosclerosis via many important intracellular mechanisms. CypA can cause injury to and apoptosis of endothelial cells, leading to dysfunction of the endothelium. CypA may also induce the activation and migration of leukocytes, producing proinflammatory cytokines that promote inflammation in blood vessels. In addition, CypA can promote the proliferation of monocytes/macrophages and vascular smooth muscle cells, leading to the formation of foam cells and the remodelling of the vascular wall. Studies investigating the roles of CypA in atherosclerosis may provide new direction for preventive and interventional treatment strategies in atherosclerosis.

Keywords: Atherosclerosis; CD147; Cyclophilin A.

Figure 1)

Immunostaining of cyclophilin A (CypA) in atherosclerotic plaques from ApoE^−/− mice. Sections of aortic sinus lesions of ApoE^−/− mice after 12 weeks of Western diet were stained with hematoxylin-eosin or polyclonal anti-CypA antibodies. A and C Hematoxylin-eosin stain (original magnification ×10 and ×40, respectively). B and D CypA staining with anti-CypA antibody (original magnification ×10 and ×40, respectively). Solid arrowhead indicates vascular smooth muscle cells in media, solid arrow indicates cholesterol clefts, open arrowhead indicates extracellularly near the elastic lamina, and open arrow indicates endothelial cells. Results are representative of four vessels (9). Reproduced with permission from reference

Figure 2)

Ribbon representation of Cyclophilin A (CypA). Cyclosporine A (CsA) – Calcineurin (Cn). Colour codes are CnA, gold; CnB, cyan; CsA, green; CypA, red; Zn²⁺ and Fe³⁺, pink; and calcium, blue. The residues from Cn involved in binding of CypA-CsA are shown as blue spheres (17). Reproduced with permission from reference

Figure 3)

Scheme of the CD147 molecule. CD147 is a transmembrance glycoprotein composed of an extracellular domain of 185 residues, a 24-residue transmembrance domain and a 39-amino acid cytoplasmic region. Three N-linked glycosylation sites critical to the function of CD147 have been identified with CD47 immunoglobulin domains. Three N-linked oligosaccharides are shown by helixes (31). CD Cytoplasmic domain; ECI First extracellular immunoglobulin domain; ECII Second extracellular immunoglobulin domain; TD Transmembrane domain. Reproduced with permission from reference

Figure 4)

Various signalling pathways that cyclophilin A (CypA) mediates. CypA mediates a variety of signalling pathways involving mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-κB) and JAK/STAT to regulate various pathological processes in atherogenesis