Cyclophilin A: a key player for human disease

Abstract

Cyclophilin A (CyPA) is a ubiquitously distributed protein belonging to the immunophilin family. CyPA has peptidyl prolyl cis-trans isomerase (PPIase) activity, which regulates protein folding and trafficking. Although CyPA was initially believed to function primarily as an intracellular protein, recent studies have revealed that it can be secreted by cells in response to inflammatory stimuli. Current research in animal models and humans has provided compelling evidences supporting the critical function of CyPA in several human diseases. This review discusses recently available data about CyPA in cardiovascular diseases, viral infections, neurodegeneration, cancer, rheumatoid arthritis, sepsis, asthma, periodontitis and aging. It is believed that further elucidations of the role of CyPA will provide a better understanding of the molecular mechanisms underlying these diseases and will help develop novel pharmacological therapies.

Figure 1

CyPA is involved in AAA formation. Ang II induces ROS formation; this in turn determines the release of CyPA from VSMC. Extracellular CyPA contributes to the recruitment of inflammatory cells in the aneurysm site and the activation of MMPs that degrade the extracellular matrix. CyPA itself induces ROS formation by a positive feedback loop

Figure 2

CyPA contributes to atherosclerosis formation. As atherosclerosis progresses, inflammation and ROS induce the release of CyPA from VSMC, EC and macrophages. Intracellular CyPA, as well as extracellular CyPA, influence LDL uptake by regulating the expression of scavenger receptors on the vessel wall. Also, CyPA induces inflammation of EC by increasing adhesion molecule expression and decreasing eNOS expression. In addition, CyPA increases the apoptosis of EC. Finally, CyPA induces the recruitment of inflammatory cells in atherosclerotic lesions

Figure 3

CyPA effects on EC, VSMC and macrophages. CyPA is secreted in response to ROS. Extracellular CyPA increases DNA synthesis and inhibits apoptosis in VSMC. In contrast, CyPA stimulates EC apoptosis, stimulates the expression of adhesion molecules including E-selectin and VCAM-1. Also, extracellular CyPA induces a pro-inflammatory status in macrophages by stimulating cytokines and chemokines production as well as inducing the activation of MMP-9 and decreasing apoptosis. These effects induce inflammation, EC dysfunction, neointimal formation thereby accelerating vascular remodeling, AAA and atherosclerosis

Figure 4

CyPA induces cancer growth. Apoptosis and hypoxia, through the activation of p53 and HIF1α, upregulate CyPA expression. This in turn stabilizes p53 protein. CyPA is also secreted by cancer cells and promotes cancer growth, metastasis and drug resistance. Anti-cancer drugs, such as DAC and 5-FU, decrease CyPA expression and thus block cancer progression. However, CyPA upregulation also decreases cisplatin-induced cell death suggesting that CyPA may lead to drug resistance

Figure 5

CyPA promotes neurodegeneration. ApoE2 and ApoE3 secreted by astrocytes, but not ApoE4, stimulates the low-density lipoprotein receptor-related protein 1 (LRP1) on pericytes. This event suppresses the pro-inflammatory pathway orchestrated by CyPA that leads to NF-kB and MMP-9 activation. As a consequence, the MMP-9-mediated degradation of tight junction and basement membrane proteins that causes BBB breakdown and neuronal dysfunction is inhibited