Cellular Biology |
From the Center for Cardiovascular Research (Z.-G.J., M.G.M., D.-F. L., C.Y., J.H., B.C.B.), University of Rochester, Rochester, NY, and Department of Biochemistry (Y,-A.S., J.D.L.), Emory University, Atlanta, Ga.
Correspondence to Bradford C. Berk, MD, PhD, University of Rochester, Department of Medicine, Box MED, Rochester, NY 14642. E-mail bradford_berk{at}urmc.rochester.edu\\ © 2000 American Heart Association, Inc.
| Abstract |
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Key Words: oxidative stress cyclophilin secretion mitogen-activated protein kinase smooth muscle cells
| Introduction |
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Increasing evidence suggests that secretion of growth factors in response to VSMC agonists mediates their mitogenic activity. For example, epiregulin, an epidermal growth factorrelated 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 platelet-derived growth factor12 13 and transforming growth factor-ß.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 mechanisms by stimulating ERK1/2 activity. In the present study, we report that cyclophilin A (CyPA) is an important secreted oxidative stress-induced factor, because it is secreted from rat VSMC in response to ROS and from fibroblasts transfected with mox1 [a superoxide generating homolog of the phagocyte NAD(P)H oxidase catalytic subunit]. Furthermore, we show that secreted CyPA stimulates ERK1/2, increases DNA synthesis, and inhibits nitric oxideinduced apoptosis in VSMCs. Finally, we demonstrate that immunostaining of CyPA is dramatically increased in balloon-injured rat carotid, with a time course that parallels neointima formation. These results suggest an important role for CyPA in the pathogenesis of vascular diseases.
| Materials and Methods |
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Preparation of Conditioned Medium
VSMCs were washed 3 times with HBSS (in mmol/L): NaCl
130, KCl 5, CaCl2 1.5,
MgCl2 1, HEPES 20, and pH 7.4), and equilibrated
in HBSS for 1 hour. Cells were then exposed to 1 µmol/L LY83583
(Calbiochem) or HBSS only for 2 hours. Conditioned medium from
LY83583-stimulated cells (LY-CM) or control medium from HBSS-incubated
cells (Ctl-CM) was then collected and centrifuged at
800g at 4°C for 10 minutes to remove cell debris.
LY-CM or Ctl-CM was concentrated 100-fold by using a Centricon Plus-80
filter (Millipore Inc) to yield concentrated LY-CM or concentrated
Ctl-CM.
Immunodepletion
Concentrated conditioned medium was incubated with
rabbit anti-CyPA polyclonal antibody (1:100 dilution [Biomol Research
Laboratories]) or an equal amount of normal rabbit serum for 22 hours
and then incubated with protein A-agarose (Life Technologies) for 2
hours on a roller system at 4°C. The supernatants and control medium
were applied to stimulate VSMCs, and ERK1/2 activity was analyzed by
Western blot.
Rat Carotid Injury and
Immunohistochemistry
Male Sprague-Dawley rats (350 to 400 g [Charles
River Laboratories, Wilmington, Mass]) were used. The surgical
procedures and immunohistochemistry were performed as previously
described.17
Paraffin-embedded rat carotids in 5-µm sections were deparaffinized
and boiled for 10 minutes in 10 mmol/L citrate buffer, pH 6, and then
blocked with 5% normal goat serum for 30
minutes.17 Rabbit
polyclonal antibody for cyclophilin A (1:1000 dilution [Biomol
Research Laboratories]) and rat adsorbed biotinylated goat antirabbit
secondary antibody (1:250 dilution [Vector]) were used, followed by
30-minute incubation in Vectastain ABC-AP (Vector) and 25-minute
development in the nonquenching fluorescent alkaline phosphatase
substrate Vector Red.
Other Techniques
Western blot
analysis,18 19
DNA synthesis,20 MTT
assay for cell
viability,21 22
and determination of
apoptosis23 were
performed as previously described.
Statistical Analysis
Data are presented as mean±SD for all experiments
that were performed at least 3 times. Significant differences were
determined by Students t test
(P<0.05).
| Results |
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Purification of SOXF from conditioned medium by sequential
chromatography suggested that proteins of the cyclophilin family might
act as a SOXF.21
CyPA is an abundant cytosolic protein that is the main target of the
immunosuppressive drug cyclosporine A (CsA). Recently, CyPA has been
reported to be secreted (for example, from
lipopolysaccharide-stimulated
macrophages).24 To
prove that CyPA is a SOXF, Western blot analysis was performed with
antibodies specific for CyPA (both the polyclonal CyPA antibody and
monoclonal antibody mAb7F1 yielded similar results). CyPA was detected
in LY-CM but not Ctl-CM
(Figure 2A
). The secretion of CyPA is specific, because no
-actin or c-raf-1 was present in LY-CM (Figure 2A
), which are abundant cytoskeletal and cytosolic
proteins in VSMCs, respectively. In addition, catalase, Tiron, and DPI
(but not MnTBAP) inhibited the secretion of CyPA (Figure 2B
). H2O2 also stimulated CyPA
secretion from VSMCs (Figure 2B
). These results showed that CyPA is secreted from
VSMCs in response to oxidative stress and is a candidate SOXF. To
estimate the concentration of CyPA present in LY-CM, Western blot
analysis was performed using known concentrations of human recombinant
CyPA (hrCyPA) as a standard. The intensity of Western blot
immunoreactivity analyzed by densitometry was linear in the range used
(least squares regression yielded the following equation: y=
4104.5x+105.5, R2=0.98). On
the basis of this comparison, the CyPA concentration in conditioned
medium is
5 nmol/L.
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To determine the extent to which secreted CyPA contributes
to ERK1/2 activation by LY83583, CyPA in concentrated LY-CM was
immunodepleted with anti-CyPA antibody (Figure 2C
). Stimulation of VSMC by concentrated LY-CM
increased ERK1/2 activity by 7.4±1.8-fold (Figure 2D
). Immunodepletion of CyPA significantly inhibited
ERK1/2 activation (51±12% decrease, P<0.01, n=4),
whereas immunodepletion with preimmune serum had no significant effect (Figure 2D
).
These findings indicate that CyPA is a SOXF that
accounts, in part, for the late-phase ERK1/2 activation stimulated by
LY83583.
To strengthen the link between oxidative stress, CyPA
expression and secretion, and cell growth, we studied cells stably
transfected with mox1. In comparison with cells
transfected with vector alone (NEF2), mox1-transfected
cells (YA28) produce significantly greater amounts of
O2- and grow faster
and to a greater cell
density.16 The
antioxidant N-acetyl cysteine (NAC) inhibited
the growth of the mox1-transfected
cells.16 The
expression of CyPA was approximately 2-fold increased in YA28 cells
(Figure 3A
). However, the greatest difference was a >10-fold
increase in the level of CyPA secreted by YA28 cells compared with NEF2
cells (Figure 3B
). Importantly, the secretion of CyPA was
completely inhibited by treating cells with 20 mmol/L NAC, consistent
with ROS as an essential mediator for CyPA secretion
(Figure 3B
).
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To determine additionally the ability of CyPA to stimulate
ERK1/2 activation in VSMC, hrCyPA was studied. The preparation of
hrCyPA used for these studies was highly purified, as shown by
silver stain analysis, which revealed that >95% of total protein
migrated at a molecular weight of 18 kDa, consistent with CyPA
(Figure 4A
). hrCyPA stimulated ERK1/2 activation in VSMC in a
concentration-dependent manner, with an
EC50 of 0.25 nmol/L
(Figure 4B
). Stimulation of ERK1/2 was not attributable
to contamination by lipopolysaccharide, because heat treatment of
hrCyPA abrogated its stimulating activity. The time course for ERK1/2
activation by 10 nmol/L hrCyPA (Figure 4C
) was similar to that observed with conditioned
medium (Figure 1F
), with peak at 10 minutes.
|
Peptidyl-Prolyl Isomerase Activity Is
Required for CyPA-Induced ERK1/2 Activation
CyPA is a member of the immunophilin family,
which possess peptidyl-prolyl isomerase (PPIase) activity. CsA is an
immunosuppressive drug that strongly inhibits the PPIase activity of
CyPA. To investigate whether PPIase activity is required for
CyPA-induced ERK1/2 activation, hrCyPA was incubated with CsA for 30
minutes at 4°C and then applied to VSMC. CsA inhibited hrCyPA-induced
ERK1/2 activation
(Figure 5A
) but had no effect on Angiotensin IIinduced
ERK1/2 activation
(Figure 5B
). Importantly, CsA significantly inhibited ERK1/2
activation by LY-CM, indicating that cyclophilins present in LY-CM are
biologically active (Figure 5C
). Taken together, these results indicate that
PPIase activity is involved in ERK1/2 activation by
CyPA.
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Cyclophilin A Stimulates VSMC Growth and
Protects VSMC Against Apoptosis
To measure the potential growth promoting effects of
CyPA secreted from VSMC, we studied the effects of LY-CM and hrCyPA on
VSMC DNA synthesis. LY-CM significantly stimulated DNA synthesis in
VSMC (3-fold increase versus 0.1% serum) assayed by
[3H]thymidine incorporation (Figure 6A
). In contrast, Ctl-CM had no mitogenic activity (Figure 6A
). In addition, 10 nmol/L hrCyPA also significantly
stimulated DNA synthesis (2-fold increase versus 0.1% serum, Figure 6B
). Thus, CyPA contributes significantly to the
growth promoting activity present in LY-CM.
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To determine whether CyPA prevents VSMC apoptosis, we used
sodium nitroprusside (SNP), which was shown to induce VSMC
apoptosis.25 26
Incubating VSMC with 1 mmol/L SNP for 24 hours decreased cell viability
to 19.4% of control, measured with a modified MTT assay
(Figure 7A
). Addition of 10 nmol/L hrCyPA in the presence of
1 mmol/L SNP blocked apoptosis, with cell viability returning to 47%
of control (Figure 7A
). In response to 0.5 mmol/L SNP for 24 hours,
10.3% of VSMCs were apoptotic as measured by nuclear morphology
after DAPI staining (Figure 7B
), consistent with previous
reports.25 26
Addition of either LY-CM or CyPA significantly inhibited apoptosis
induced by 0.5 mmol/L SNP, with decreases of 91% and 55%,
respectively (Figure 7C
).
|
Cyclophilin A Expression and Secretion Are
Increased In Vivo by Vascular Injury
Oxidative stress has been shown to mediate many of the
changes that lead to vascular lesion formation in
vivo.1 Because the
rat carotid balloon injury model is associated with ROS generation and
neointima formation develops largely as a consequence of VSMC
proliferation,27 28
we examined the time course of CyPA expression in this model.
Morphological analysis demonstrated formation of a neointima within 1
week after injury
(Figure 8
). Immunoreactive CyPA was present at low level in
sections of sham-operated arteries (Figure 8
, top panel). By 24 hours after balloon injury,
abundant CyPA immunoreactivity was present throughout the vessel, with
particularly strong staining in the adventitia (Figure 8
, second panel). By 4 days, the majority of the CyPA
staining was localized to the first cells forming the neointima and the
most luminal medial VSMC layers (Figure 8
, third panel). After 1 week of injury, when a
substantial neointima had formed, CyPA immunoreactivity was highest in
the neointima and most luminal medial VSMC (Figure 8
, bottom panel). No staining was observed in
sections incubated with normal rabbit serum (data not
shown).
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| Discussion |
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Understanding the mechanisms by which ROS modulate cell function is important for cardiovascular disease, because ROS are increased in ischemia-reperfusion, hypertension, and atherosclerosis. It has become clear that atherogenesis demonstrates cellular and molecular responses that resemble an inflammatory disease.29 Monocytes, polymorphonuclear leukocytes, and T lymphocytes are markedly increased in regions of human atheroma.30 31 ROS produced by white blood cells in the vessel wall in vivo is unknown; at sites of inflammation, production of ROS is enhanced, and H2O2 levels have been estimated at 0.1 to 1.0 mmol/L,32 33 34 35 36 which is greater than values used in this study. Because antioxidants such as vitamin E and probucol have had significant beneficial effects on coronary events37 and restenosis after angioplasty,38 it will be important to clarify the mechanisms by which ROS contribute to the initiation and progression of cardiovascular disease.29
In the present study, we tested several approaches to generate ROS, including 200 µmol/L H2O2 and 1 µmol/L LY83583, 50 µmol/L menadione, and 100 µmol/L xanthine plus 1 U/mL xanthine oxidase. Concentrations used in the present study are similar to those in a large number of studies in the literature.5 39 40 41 42 Although this level of ROS is rarely achieved in normal physiological conditions, such levels may be present transiently in pathophysiological conditions, such as inflammation and vessel injury. In addition, we showed that CyPA was induced and secreted in cells transfected with the O2-generating enzyme mox-1. The level of oxidative stress in mox1-transfected cells is quite low,16 indicating the physiological relevance of the present findings.
The mechanisms that regulate CyPA secretion and expression are unknown. Our findings that antioxidants (except SOD) inhibited late phase ERK1/2 activation and CyPA secretion in response to LY83583, as well as our results with mox1-transfected cells, support the hypothesis that increased ROS stimulate expression and secretion of CyPA. Indeed, induction of cyclophilins together with other stress proteins has been shown in endothelial cells treated with exogenous oxidants.43 Our data suggest that hydrogen peroxide is the predominant ROS responsible for CyPA induction and ERK activation, because hydrogen peroxide leads to CyPA induction and catalase inhibits secretion of CyPA and late ERK activation, whereas SOD stimulates these events. Furthermore, there also seems to be a relationship in vivo among inflammation, ROS, and cyclophilin release, as shown by the high CyPA levels in serum from patients with human immunodeficiency virus type-1, rheumatoid arthritis, and sepsis.44 45 46 Because these diseases are usually accompanied with ROS generation by neutrophils, lymphocytes, and vessel wall cells, it is possible that ROS may stimulate the CyPA secretion and expression in vivo. In the balloon-injured carotid model, we found dramatic increases in CyPA expressed in the neointima. The time course and location of CypA expression within the balloon-injured artery is consistent with this hypothesis, because balloon injury is associated with increased ROS production.27 47
Although increasing evidence shows that cyclophilins are secreted, the present study is the first to show that a cyclophilin acts as a growth factor. We showed that CyPA activated ERK1/2, increased DNA synthesis, and protected cells against apoptosis, suggesting that CyPA shares common signal pathways with growth factors. We have also observed that CyPA increased intracellular calcium in VSMCs and BAPTA-AM (an intracellular calcium chelator) abrogated ERK1/2 activation in response to CyPA (data not shown). In addition to VSMC, we observed that CyPA stimulated ERK1/2 activation in mox1-transfected NIH3T3 cells as well as in endothelial cells and lymphocytes (data not shown). These results suggest a broad role for CyPA as an extracellular signal mediator.
Cyclophilins possess PPIase activity.48 49 However, the PPIase activity of these proteins is not involved in their immunosuppressive effects,50 and the biological functions of this enzymatic activity remain poorly understood. Our finding that CsA inhibits CyPA-induced ERK1/2 suggests a role for PPIase activity in mediating signal transduction. In preliminary experiments, we have observed that although a mutant CyPA (R55A) is 1000-fold less active as a PPIase, it failed to stimulate ERK1/2 activation (data not shown). Taken together, these results indicate that the PPIase activity of CyPA is required for ERK1/2 activation and suggest the existence of a plasma membrane receptor that may be modified or activated by PPIase activity. In support of this concept, host-derived CyPA was shown to be incorporated into human immunodeficiency virus type-1 virions, and this incorporation was essential for viral infectivity. Because infectivity was inhibited by CsA, the results suggested that an interaction with a cellular receptor for CyPA was important in infectivity.51 Thus, additional characterization of the nature of the CyPA receptor and the role of PPIase activity will provide insights into the physiological importance of these novel functions of CyPA.
Analysis of LY-CM showed that several factors were secreted
from VSMC in response to oxidative
stress.21 In this
study, we proved that CyPA was a SOXF that played an important role in
ROS-induced late phase ERK1/2 activation and cell growth.
Immunodepletion of CyPA inhibited LY-CMinduced ERK1/2 activation by
50%
(Figure 2
). hrCyPA-induced ERK1/2 activation was totally
blocked by CsA
(Figure 5A
), but LY-CMinduced ERK1/2 activation was only
inhibited by 50% with CsA
(Figure 5C
). hrCyPA was also
50% as effective as LY-CM in
preventing apoptosis
(Figure 7
). Taken together, these results suggest that other
factors in LY-CM likely contribute to ROS-induced late phase ERK1/2
activation, DNA synthesis, and inhibition of apoptosis.
In summary, the present study demonstrates a novel role for CyPA as a secreted redox-sensitive mediator and VSMC growth factor. Understanding the mechanisms by which ROS stimulate CyPA secretion and CyPA stimulates cell growth and inhibits apoptosis should provide important insights into the cellular response to oxidative stress.
| Acknowledgments |
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Received May 10, 2000; revision received September 15, 2000; accepted September 21, 2000.
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Y. Yang, N. Lu, J. Zhou, Z.-n. Chen, and P. Zhu Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis Rheumatology, September 1, 2008; 47(9): 1299 - 1310. [Abstract] [Full Text] [PDF] |
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S. Perez and V. Weis Cyclophilin and the Regulation of Symbiosis in Aiptasia pallida Biol. Bull., August 1, 2008; 215(1): 63 - 72. [Abstract] [Full Text] [PDF] |
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C.-Y. Chen, B.-C. Lee, H.-C. Hsu, H.-J. Lin, C.-L. Chao, Y.-H. Lin, Y.-L. Ho, and M.-F. Chen A proteomic study of the effects of ramipril on post-infarction left ventricular remodelling in the rabbit Eur J Heart Fail, August 1, 2008; 10(8): 740 - 748. [Abstract] [Full Text] [PDF] |
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K. Satoh, T. Matoba, J. Suzuki, M. R. O'Dell, P. Nigro, Z. Cui, A. Mohan, S. Pan, L. Li, Z.-G. Jin, et al. Cyclophilin A Mediates Vascular Remodeling by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation Circulation, June 17, 2008; 117(24): 3088 - 3098. [Abstract] [Full Text] [PDF] |
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J. M. Damsker, M. I. Bukrinsky, and S. L. Constant Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A J. Leukoc. Biol., September 1, 2007; 82(3): 613 - 618. [Abstract] [Full Text] [PDF] |
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R. Pakula, A. Melchior, A. Denys, C. Vanpouille, J. Mazurier, and F. Allain Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis Glycobiology, May 1, 2007; 17(5): 492 - 503. [Abstract] [Full Text] [PDF] |
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A. Shamaei-Tousi, J. P. Halcox, and B. Henderson Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease Cardiovasc Res, April 1, 2007; 74(1): 19 - 28. [Abstract] [Full Text] [PDF] |
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X. Chen, J. Lin, T. Kanekura, J. Su, W. Lin, H. Xie, Y. Wu, J. Li, M. Chen, and J. Chang A Small Interfering CD147-Targeting RNA Inhibited the Proliferation, Invasiveness, and Metastatic Activity of Malignant Melanoma Cancer Res., December 1, 2006; 66(23): 11323 - 11330. [Abstract] [Full Text] [PDF] |
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P. Ortega-Saenz, A. Pascual, R. Gomez-Diaz, and J. Lopez-Barneo Acute Oxygen Sensing in Heme Oxygenase-2 Null Mice J. Gen. Physiol., October 1, 2006; 128(4): 405 - 411. [Abstract] [Full Text] [PDF] |
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W. M. Gwinn, J. M. Damsker, R. Falahati, I. Okwumabua, A. Kelly-Welch, A. D. Keegan, C. Vanpouille, J. J. Lee, L. A. Dent, D. Leitenberg, et al. Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention J. Immunol., October 1, 2006; 177(7): 4870 - 4879. [Abstract] [Full Text] [PDF] |
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S. Semba and K. Huebner Protein Expression Profiling Identifies Cyclophilin A as a Molecular Target in Fhit-Mediated Tumor Suppression Mol. Cancer Res., August 1, 2006; 4(8): 529 - 538. [Abstract] [Full Text] [PDF] |
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K. R. Stenmark, N. Davie, M. Frid, E. Gerasimovskaya, and M. Das Role of the Adventitia in Pulmonary Vascular Remodeling Physiology, April 1, 2006; 21(2): 134 - 145. [Abstract] [Full Text] [PDF] |
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J. Suzuki, Z.-G. Jin, D. F. Meoli, T. Matoba, and B. C. Berk Cyclophilin A Is Secreted by a Vesicular Pathway in Vascular Smooth Muscle Cells Circ. Res., March 31, 2006; 98(6): 811 - 817. [Abstract] [Full Text] [PDF] |
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B. A. Howard, R. Furumai, M. J. Campa, Z. N. Rabbani, Z. Vujaskovic, X.-F. Wang, and E. F. Patz Jr. Stable RNA Interference-Mediated Suppression of Cyclophilin A Diminishes Non-Small-Cell Lung Tumor Growth In vivo Cancer Res., October 1, 2005; 65(19): 8853 - 8860. [Abstract] [Full Text] [PDF] |
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C. Wong and Z.-G. Jin Protein Kinase C-dependent Protein Kinase D Activation Modulates ERK Signal Pathway and Endothelial Cell Proliferation by Vascular Endothelial Growth Factor J. Biol. Chem., September 30, 2005; 280(39): 33262 - 33269. [Abstract] [Full Text] [PDF] |
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K. Arora, W. M. Gwinn, M. A. Bower, A. Watson, I. Okwumabua, H. R. MacDonald, M. I. Bukrinsky, and S. L. Constant Extracellular Cyclophilins Contribute to the Regulation of Inflammatory Responses J. Immunol., July 1, 2005; 175(1): 517 - 522. [Abstract] [Full Text] [PDF] |
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H. Cai NAD(P)H Oxidase-Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease Circ. Res., April 29, 2005; 96(8): 818 - 822. [Abstract] [Full Text] [PDF] |
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Z.-G. Jin, C. Wong, J. Wu, and B. C. Berk Flow Shear Stress Stimulates Gab1 Tyrosine Phosphorylation to Mediate Protein Kinase B and Endothelial Nitric-oxide Synthase Activation in Endothelial Cells J. Biol. Chem., April 1, 2005; 280(13): 12305 - 12309. [Abstract] [Full Text] [PDF] |
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B. Stratmann and D. Tschoepe Pathobiology and cell interactions of platelets in diabetes Diabetes and Vascular Disease Research, February 1, 2005; 2(1): 16 - 23. [Abstract] [PDF] |
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S. Watanabe, S. Tsuruoka, S. Vijayakumar, G. Fischer, Y. Zhang, A. Fujimura, Q. Al-Awqati, and G. J. Schwartz Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin Am J Physiol Renal Physiol, January 1, 2005; 288(1): F40 - F47. [Abstract] [Full Text] [PDF] |
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Z.-J. Chen, M. Vetter, G.-D. Chang, S. Liu, D. Che, Y. Ding, S. S. Kim, and C.-H. Chang Cyclophilin A Functions as an Endogenous Inhibitor for Membrane-Bound Guanylate Cyclase-A Hypertension, December 1, 2004; 44(6): 963 - 968. [Abstract] [Full Text] [PDF] |
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S. Gu, Z. Liu, S. Pan, Z. Jiang, H. Lu, O. Amit, E. M. Bradbury, C.-A. A. Hu, and X. Chen Global Investigation of p53-induced Apoptosis Through Quantitative Proteomic Profiling Using Comparative Amino Acid-coded Tagging Mol. Cell. Proteomics, October 1, 2004; 3(10): 998 - 1008. [Abstract] [Full Text] [PDF] |
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J. Liu, A. Ormsby, N. Oja-Tebbe, and P. J. Pagano Gene Transfer of NAD(P)H Oxidase Inhibitor to the Vascular Adventitia Attenuates Medial Smooth Muscle Hypertrophy Circ. Res., September 17, 2004; 95(6): 587 - 594. [Abstract] [Full Text] [PDF] |
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Z.-G. Jin, A. O. Lungu, L. Xie, M. Wang, C. Wong, and B. C. Berk Cyclophilin A Is a Proinflammatory Cytokine that Activates Endothelial Cells Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1186 - 1191. [Abstract] [Full Text] [PDF] |
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Z G Jin and B C Berk SOXF: redox mediators of vascular smooth muscle cell growth Heart, May 1, 2004; 90(5): 488 - 490. [Full Text] [PDF] |
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S.-H. Kim, S. M. Lessner, Y. Sakurai, and Z. S. Galis Cyclophilin A as a Novel Biphasic Mediator of Endothelial Activation and Dysfunction Am. J. Pathol., May 1, 2004; 164(5): 1567 - 1574. [Abstract] [Full Text] [PDF] |
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J. A. Coppinger, G. Cagney, S. Toomey, T. Kislinger, O. Belton, J. P. McRedmond, D. J. Cahill, A. Emili, D. J. Fitzgerald, and P. B. Maguire Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions Blood, March 15, 2004; 103(6): 2096 - 2104. [Abstract] [Full Text] [PDF] |
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R. Ramer, U. Weinzierl, B. Schwind, K. Brune, and B. Hinz Ceramide Is Involved in R(+)-Methanandamide-Induced Cyclooxygenase-2 Expression in Human Neuroglioma Cells Mol. Pharmacol., November 1, 2003; 64(5): 1189 - 1198. [Abstract] [Full Text] [PDF] |
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P. Gromov, G. L. Skovgaard, H. Palsdottir, I. Gromova, M. Ostergaard, and J. E. Celis Protein Profiling of the Human Epidermis from the Elderly Reveals Up-regulation of a Signature of Interferon-{gamma}-induced Polypeptides That Includes Manganese-superoxide Dismutase and the p85{beta} Subunit of Phosphatidylinositol 3-Kinase Mol. Cell. Proteomics, February 1, 2003; 2(2): 70 - 84. [Abstract] [Full Text] [PDF] |
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F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF] |
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S. Misumi, T. Fuchigami, N. Takamune, I. Takahashi, M. Takama, and S. Shoji Three Isoforms of Cyclophilin A Associated with Human Immunodeficiency Virus Type 1 Were Found by Proteomics by Using Two-Dimensional Gel Electrophoresis and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry J. Virol., September 3, 2002; 76(19): 10000 - 10008. [Abstract] [Full Text] [PDF] |
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J. Fukuzawa, J. Nishihira, N. Hasebe, T. Haneda, J. Osaki, T. Saito, T. Nomura, T. Fujino, N. Wakamiya, and K. Kikuchi Contribution of Macrophage Migration Inhibitory Factor to Extracellular Signal-regulated Kinase Activation by Oxidative Stress in Cardiomyocytes J. Biol. Chem., July 5, 2002; 277(28): 24889 - 24895. [Abstract] [Full Text] [PDF] |
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V. Yurchenko, G. Zybarth, M. O'Connor, W. W. Dai, G. Franchin, T. Hao, H. Guo, H.-C. Hung, B. Toole, P. Gallay, et al. Active Site Residues of Cyclophilin A Are Crucial for Its Signaling Activity via CD147 J. Biol. Chem., June 14, 2002; 277(25): 22959 - 22965. [Abstract] [Full Text] [PDF] |
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D. A. Bosco, E. Z. Eisenmesser, S. Pochapsky, W. I. Sundquist, and D. Kern Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A PNAS, April 16, 2002; 99(8): 5247 - 5252. [Abstract] [Full Text] [PDF] |
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F. Allain, C. Vanpouille, M. Carpentier, M.-C. Slomianny, S. Durieux, and G. Spik Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix PNAS, February 20, 2002; (2002) 52284899. [Abstract] [Full Text] [PDF] |
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F. J. Miller Jr Adventitial Fibroblasts : Backstage Journeymen Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 722 - 723. [Full Text] [PDF] |
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F. Allain, C. Vanpouille, M. Carpentier, M.-C. Slomianny, S. Durieux, and G. Spik Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix PNAS, March 5, 2002; 99(5): 2714 - 2719. [Abstract] [Full Text] [PDF] |
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D. A. Bosco, E. Z. Eisenmesser, S. Pochapsky, W. I. Sundquist, and D. Kern Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A PNAS, April 16, 2002; 99(8): 5247 - 5252. [Abstract] [Full Text] [PDF] |
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