Cyclophilin A as a Novel Biphasic Mediator of Endothelial Activation and Dysfunction

Abstract

Inflammation-mediated endothelial cell (EC) dysfunction likely contributes to the pathogenesis of several vascular diseases including atherosclerosis. We found that stimulation of human umbilical vein ECs with lipopolysaccharide induced secretion of cyclophilin (CyPA) an intracellular protein belonging to the immunophilin family. We then found that when added exogenously CyPA has direct effects on ECs in vitro. At low concentrations (10 to 100 ng/ml) CyPA increased EC proliferation, migration, invasive capacity, and tubulogenesis. Gelatin zymography indicated increased secretion of active matrix metalloproteinase-2, a mediator of cell migration and angiogenesis. At high concentrations (eg, 2 g/ml) CyPA had opposite effects, decreasing EC migration and viability, possibly in relation to induction of Toll-like receptor-4 expression, detected by immunocytochemistry and flow cytometry. In vivo CyPA expression was not detectable in the luminal ECs of normal mouse carotid arteries but was rapidly induced after systemic lipopolysaccharide injection. In an experimental mouse model of atherosclerosis, CyPA expression was detected in the ECs of neocapillaries of carotid artery lesions, supporting its association with pathological angiogenesis suggested by our in vitro results. In conclusion, we found that CyPA has a biphasic activity on ECs in vitro and is up-regulated in vivo in ECs under pathological states. Our results suggest that CyPA is a novel paracrine and autocrine modulator of EC functions in immune-mediated vascular disease.

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

“…Increased levels of extracellular cyclophilins (mostly CypA) have been documented in many inflammatory diseases, and their role in disease pathogenesis has been verified in a variety of animal models of human diseases, including rheumatoid arthritis, sepsis, asthma, atherosclerosis and a number of viral infections (33,34). Similarly, we reported a marked inhibitory effect of an extracellularly restricted inhibitor of the peptidyl prolyl isomerase activity of cyclophilins, the highly branched CsA-like molecule MM218, on the inflammatory response in a mouse model of allergic lung inflammation (13).…”

“…Indeed, several reports have demonstrated activation of the CD147-induced signaling pathways by CypA circulating in extracellular media in a number of inflammatory diseases (31). CypA has been shown to be secreted by different types of cells in response to inflammatory stimuli and oxidative stress (32)(33)(34)(35)(36). While the cells responsible for secretion of extracellular cyclophilin in our BA model have not been identified, hepatocytes may be involved as these cells have been shown to secrete CypA in response to infection by another virus, hepatitis B (37).…”

Differential Expression of Cyclophilin A and EMMPRIN in Developing Molars of Rats

“…This molecule is involved in the adhesion of monocytes/macrophages to the extracellular matrix (Yang et al, 2008) and the migration of murine bone marrow cells (Khromykh et al, 2007). In addition, the secreted form modulates osteoblastic activity (Andersen et al, 2003) as well as the functions of endothelial cells via paracrine and autocrine modes (Kim et al, 2004).…”

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

“…These tissue changes were validated by western blot. Recent studies have demonstrated that extracellular cyclophilin is proinflammatory via the CD147 receptor and that anti-CD147 antibodies are anti-inflammatory (12,13,14,15,16). Administration of anti-CD147 antibodies significantly reduced sepsis-induced acute renal failure and reduced both pro and anti inflammatory cytokine production.…”

“…Cyclophilin is released by cells in response to inflammation and elevated serum levels have been demonstrated in humans with severe sepsis (35). Cyclophilin has pro-inflammatory actions, for example as a chemotactic agent for inflammatory cells (13) and an activator of endothelial cells (14,15). Therefore, we choose this protein as a potential therapeutic target.…”