Cyclophilin A Is a Secreted Growth Factor Induced by Oxidative Stress

Abstract

Abstract-Reactive oxygen species have been implicated in the pathogenesis of atherosclerosis, hypertension, and restenosis, in part by promoting vascular smooth muscle cell (VSMC) growth. Many VSMC growth factors are secreted by VSMC and act in an autocrine manner. Here we demonstrate that cyclophilin A (CyPA), a member of the immunophilin family, is secreted by VSMCs in response to oxidative stress and mediates extracellular signal-regulated kinase (ERK1/2) activation and VSMC growth by reactive oxygen species. Human recombinant CyPA can mimic the effects of secreted CyPA to stimulate ERK1/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERK1/2 activation by CyPA. In vivo, CyPA expression and secretion are increased by oxidative stress and vascular injury. These findings are the first to identify CyPA as a secreted redox-sensitive mediator, establish CyPA as a VSMC growth factor, and suggest an important role for CyPA and enzymes with peptidyl-prolyl isomerase activity in the pathogenesis of vascular diseases. (Circ Res. 2000;87:789 -796.)Key Words: oxidative stress Ⅲ cyclophilin Ⅲ secretion Ⅲ mitogen-activated protein kinase Ⅲ smooth muscle cells R eactive oxygen species (ROS) have been implicated in the pathogenesis of atherosclerosis, hypertension, and restenosis, in part by promoting vascular smooth muscle cell (VSMC) growth. [1][2][3][4] We have previously reported that ROS stimulate VSMC growth and DNA synthesis. 5 This proliferation was associated with stimulation of protein kinases, especially the extracellular signal-regulated kinases (ERK1/2, also termed p42/44 mitogen-activated protein kinases [MAPKs]). 4 ERK1/2 are stimulated by growth factors and cytokines and play pivotal roles in cell growth and differentiation. 6,7 Activation of ERK1/2 by ROS generators, such as the napthoquinolinedione LY83583, menadione, and xanthine/xanthine oxidase as well as H 2 O 2 , was biphasic; an early peak of ERK1/2 activity was present at 5 to 10 minutes, whereas a delayed ERK1/2 activation appeared at 2 hours. 8 A similar biphasic activation of ERK1/2 has been reported for mitogens such as fibroblast growth factor. 9 Recently, the delayed ERK1/2 activation has been reported to be mediated by different mechanisms than the early ERK1/2 activation and to be critical for cell cycle progression and cell proliferation. 9,10 Increasing evidence suggests that secretion of growth factors in response to VSMC agonists mediates their mitogenic activity. For example, epiregulin, an epidermal growth factor-related growth factor, is a potent VSMC-secreted mitogen whose expression is regulated by angiotensin II, endothelin-1, and thrombin. 11 These same agonists also stimulate secretion of other growth factors, including plateletderived growth factor 12,13 and transforming growth factor-␤. 14 However, no factors have been identified as mediators of VSMC proliferation in response to ROS.We hypothesized that in response to ROS, VSMCs may secrete factors that participate in autocrine and paracrine growth mecha...

Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147

“…22 Our results suggest that CypA increases phosphorylation of ERK1/2 and p38 as early as 5 minutes in human pancreatic cancer cells. Our data provide evidence that CypA stimulates proliferation of Panc-1 cells through its cellular receptor CD147 by activating the ERK1/2 and p38 pathways, the most common signal pathways shared by other growth factors.…”

“…CypA has been shown to be a secreted growth factor induced by oxidative stress and stimulates ERK1/2 pathway and cell proliferation in vascular smooth muscle cells (VSMCs). 22 In neuronal cells, where CypA has been shown to be most highly concentrated, augmented cell proliferation of human embryonic brain cells in response to CypA stimulation was found. 23 However, studies of correlation between CypA and cancers are limited.…”

Positional cloning identifies a novel cyclophilin as a candidate amplified oncogene in 1q21

“…Another novel member of the cyclophilin family (PPIE) was ampli®ed in small cell lung cancer cell lines with L-myc ampli®cation (Kim et al, 1998). Furthermore, cyclophilin A has been suggested to be secreted and have growth factor activity under oxidative stress (Jin et al, 2000), and exposure of hepatocytes to peroxisome proliferation inducers upregulates cyclophilin A expression (Corton et al, 1998).…”

Molecular cloning and characterization of two isoforms of cyclophilin A gene from Venerupis philippinarum

“…Although CypA was originally believed to exist solely as an intracellular protein, later studies have revealed that it can be secreted by cells in response to inflammatory stimuli [20]. The clinical importance of Cyps has been implicated in diverse pathological conditions, such as HIV [21], hepatitis B and C viral infection [22], atherosclerosis [23], vascular diseases [24] and Rheumatoid Arthritis pathogenesis [25]. Recent studies also revealed that CypA could modulate HIV-1 capsid disassembly and that changes in capsid stability could influence HIV-1 sensitivity to the inhibition of CypA binding [26].…”