Plasma level of cyclophilin A is increased in patients with type 2 diabetes mellitus and suggests presence of vascular disease

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Abstract

Aims/hypothesis

Cyclophilin A, an immunophilin is secreted from human monocytes activated by high glucose. Given its role as an inflammatory mediator of vascular tissue damage associated with inflammation and oxidative stress, we examined plasma levels of cyclophilin A in normal healthy volunteers and patients with type 2 diabetes (DM), with or without coronary artery disease (CAD).

Methods

Study subjects comprised of 212 patients with DM and CAD,101 patients with diabetes, 122 patients with CAD and 121 normal healthy volunteers. Diabetes was assessed by HbA1c levels while coronary artery disease was established by a positive treadmill test and/or coronary angiography. Plasma cyclophilin A was measured using a cyclophilin A ELISA Kit. Relationship of plasma cyclophilin A levels with blood markers of type 2 diabetes, blood lipid levels and medication for diabetes and coronary artery disease were also explored.

Results

Plasma Cyclophilin levels were higher in diabetes patients with or without CAD compared to normal subjects (P < 0.001). Age, fasting blood sugar levels and HbA1C levels were positively associated with increased plasma cyclophilin. Patients using metformin had reduced levels of plasma cyclophilin (p < 0.001).Serum levels of total cholesterol, LDL cholesterol and triglycerides had no significant association with plasma cyclophilin levels. In patients with increased serum CRP levels, plasma cyclophilin A was also elevated (p = 0.016). Prevalence odds for DM, DM + CAD and CAD are higher in those with high cyclophilin values, compared to those with lower values, after adjusting for age and sex, indicating strong association of high cyclophilin values with diabetes and vascular disease.

Conclusions/interpretations

Our study demonstrates that patients with type 2 diabetes have higher circulating levels of cyclophilin A than the normal population. Plasma cyclophilin levels were increased in patients with diabetes and coronary artery disease suggesting a role of this protein in accelerating vascular disease in type 2 diabetes. Considering the evidence that Cyclophilin A is an inflammatory mediator in atherogenesis, the mechanistic role of cyclophilin A in diabetic vascular disease progression deserves detailed investigation.

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Most cited references 16

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C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.

W. Koenig, M Sund, M. Fröhlich … (1999)

Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events. We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein (CRP) with the incidence of first major coronary heart disease (CHD) event in 936 men 45 to 64 years of age. The subjects, who were sampled at random from the general population, participated in the first MONICA Augsburg survey (1984 to 1985) and were followed for 8 years. There was a positive and statistically significant unadjusted relationship, which was linear on the log-hazards scale, between CRP values and the incidence of CHD events (n=53). The hazard rate ratio (HRR) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 (95% CI, 1.29 to 2. 17). After adjustment for age, the HRR was 1.60 (95% CI, 1.23 to 2. 08). Adjusting further for smoking behavior, the only variable selected from a variety of potential confounders by a forward stepping process with a 5% change in the relative risk of CRP as the selection criterion, yielded an HRR of 1.50 (95% CI, 1.14 to 1.97). These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.

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Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.

Paul Ridker, Julie Buring, Jessie Shih … (1998)

C-reactive protein (CRP) predicts risk of myocardial infarction (MI) and stroke among apparently healthy men, but in women, virtually no data are available. CRP was measured in baseline blood samples from 122 apparently healthy participants in the Women's Health Study who subsequently suffered a first cardiovascular event and from 244 age- and smoking-matched control subjects who remained free of cardiovascular disease during a 3-year follow-up period. Women who developed cardiovascular events had higher baseline CRP levels than control subjects (P=0.0001), such that those with the highest levels at baseline had a 5-fold increase in risk of any vascular event (RR=4.8; 95% CI, 2.3 to 10.1; P=0.0001) and a 7-fold increase in risk of MI or stroke (RR=7.3; 95% CI, 2.7 to 19.9; P=0.0001). Risk estimates were independent of other risk factors, and prediction models that included CRP provided a better method to predict risk than models that excluded CRP (all P values <0.01). In stratified analyses, CRP was a predictor among subgroups of women with low as well as high risk as defined by other cardiovascular risk factors. In these prospective data among women, CRP is a strong independent risk factor for cardiovascular disease that adds to the predictive value of risk models based on usual factors alone. (Circulation. 1998;98:731-733.)

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Cyclophilin A is a secreted growth factor induced by oxidative stress.

M Melaragno, J. Lambeth, Bradford C. Berk … (2000)

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.

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Author and article information

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central

ISSN (Electronic): 1475-2840

Publication date Collection: 2014

Publication date (Electronic): 7 February 2014

Volume: 13

Page: 38

Affiliations

[1 ]Cardiovascular Disease Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India

[2 ]Achutha Menon Centre, SCTIMST, Thiruvananthapuram, India

[3 ]Madras Medical Mission, Chennai, India

[4 ]Indian Institute of Diabetes, Thiruvananthapuram, India

[5 ]PRS Hospital, Thiruvananthapuram, India

[6 ]Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India

Article

Publisher ID: 1475-2840-13-38

DOI: 10.1186/1475-2840-13-38

PMC ID: 3922405

PubMed ID: 24502618

SO-VID: 0af60da5-2faf-4ccf-b319-c893c73bf079

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Plasma level of cyclophilin A is increased in patients with type 2 diabetes mellitus and suggests presence of vascular disease

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Abstract

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Vascular Biology

Most cited references 16

C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.

Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.

Cyclophilin A is a secreted growth factor induced by oxidative stress.

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