Serum pigment epithelium-derived factor levels are independently correlated with the presence of coronary artery disease
Serum pigment epithelium-derived factor levels are independently correlated with the presence of coronary artery disease
Feifei Wang 0
Xiaojing Ma 0
Mi Zhou 0
Xiaoping Pan 0
Jie Ni 0
Yuqian Bao 0
Weiping Jia 0
0 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus , Shanghai , China
Background: Pigment epithelium-derived factor (PEDF) has been proved to be closely correlated with metabolic syndrome (MetS) and its components that are all risk factors of cardiovascular disease and may play a protective role against vascular injury and atherosclerosis. The present study was designed to investigate the relationship between serum PEDF and coronary artery disease (CAD). Methods: A total of 312 consecutive in-patients (including 228 with CAD and 197 with MetS) who underwent coronary angiography were enrolled. Serum PEDF was measured by sandwich enzyme immunoassay and used to carry out multivariate stepwise regression analysis to assess correlation with patient demographic and clinical parameters. Multiple logistic regression analysis was performed to identify factors independently correlated with CAD. Results: Patients with MetS had significantly higher levels of serum PEDF than non-MetS subjects (11.1(8.2, 14.2) vs. 10.1 (7.6, 12.4) g/mL; P < 0.05). Patients with CAD also had significantly higher serum PEDF than non-CAD subjects (11.0(8.1, 14.2) vs. 10.3(8.1, 12.8) g/mL; P < 0.05). Triglyceride (TG), C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), and hypoglycemic therapy were independently correlated with serum PEDF levels, and serum PEDF was independently positively correlated with CAD. Conclusions: Serum PEDF levels are independently positively associated with CAD in a Chinese population. Elevated PEDF may act as a protective response against vascular damage and subsequent CAD.
Atherosclerosis; Coronary angiography; Coronary artery disease; Metabolic syndrome; Pigment epitheliumderived factor
The pigment epithelium-derived factor (PEDF) belongs
to the super family of serine protease inhibitors, and the
major sources of circulating PEDF are liver and adipose
tissues [1-3]. PEDF is characterized as a multifunctional
protein possessing anti-angiogenic, anti-tumorigenic,
anti-oxidant, anti-inflammatory, anti-thrombotic, and
neuroprotective properties. Demonstrated as a highly
effective anti-angiogenic factor, PEDF not only is capable
of inhibiting vascular endothelial growth and migration,
but can also suppress secretion of angiogenic factors
[4,5] as well as activate the FAS-FAS ligand death
pathway to stimulate endothelial cell apoptosis .
Nakamura et al. reported anti-oxidative effects of PEDF,
showing that PEDF-mediated suppression of NADPH
oxidase inhibited generation of reactive oxygen species
and the subsequent neointimal hyperplasia induced by
balloon injury . Takenaka et al. also showed a
cardioprotective function by which PEDF inhibited occlusive
thrombus formation in the carotis artery of a rat model
. Finally, various studies have demonstrated the strong
anti-inflammatory activities of PEDF; for example, PEDF
was characterized both as a regulator of cytokines
expression such as monocyte chemoattractant
protein-1 and tumor necrosis factor- as well as a mediator
of macrophage and T cell function [9-11].
PEDF may rely on any of these protective properties to
manifest a counteractive mechanism during the
development of atherosclerosis and cardiovascular disease.
Recent clinical findings have revealed that PEDF levels are
closely associated with the presence of cardiovascular
disease. Circulating PEDF levels were shown to be
higher in subjects with metabolic syndrome (MetS) and
to be correlated with the extent of MetS components
[12-14]. The fact that MetS itself, and each of its
components, are important risk factors of cardiovascular
disease which has led researchers to hypothesize that
increased PEDF levels might have occurred as a
counterregulatory response to the presence of vascular injury. A
recent study showed that serum PEDF level was
independently correlated with intima-media thickness and
vascular inflammation, suggesting an association of
PEDF with subclinical atherosclerosis in at least two
aspects: morphological abnormalities of the vessel, and
inflammation in the plaques .
The above clinical findings revealed that PEDF levels
were closely associated with the presence of
cardiovascular disease, however, no study to date has focused on the
relationship between serum PEDF and coronary artery
disease (CAD). Since such data may also help to identify
PEDF as a promising therapeutic target for
atherosclerosis and cardiovascular disease [16,17], the present study
was carried out with Chinese patients who underwent
coronary angiography to investigate the association
between serum PEDF and CAD.
Materials and methods
A total of 312 participants (206 men and 106 women;
age range: 38 ~ 86 years, mean age: 66.2 10.1 years)
who were admitted to the Department of Cardiology of
Shanghai Jiao Tong University Affiliated Sixth Peoples
Hospital to undergo coronary angiography because they
have once suffered or was just suffering from chest
tightness and/or chest pain between July 2008 and January
2010 were enrolled in the study. Patients were excluded
from enrollment according to: serious hepatic or renal
dysfunction; acute myocardial infarction within the past
three months; coronary by-pass surgery or percutaneous
coronary intervention within the past six months;
congestive heart failure (defined as New York Heart
Association functional class III-IV); acute infection; or history
of malignancy. All women were postmenopausal. All
enrollees completed a standardized questionnaire to
selfreport past and present illnesses, medications, and
smoking habits. Enrollees who identified themselves as
regular smokers, or who reported smoking at least one
cigarette per day for at least the past six months, were
classified as current smokers . The study was approved
by the Ethics Committee of Shanghai Jiao Tong University
affiliated Sixth Peoples Hospital and complied with the
Declaration of Helsinki. All the subjects provided written
informed consent prior to the study participation.
According to the criteria of the 2007 Chinese Joint
Committee for Developing Chinese Guidelines on
Prevention and Treatment of Dyslipidemia in Adults ,
MetS was diagnosed if a patient had three or more of
the following: 1) central obesity, defined as waist
circumference (W) of >90 cm for men and >85 cm for women;
2) fasting triglyceride (TG) of 1.7 mmol/L, or receipt of
specific treatment for previously diagnosed
hypertriglyceridemia; 3) fasting high-density lipoprotein cholesterol
(HDL-c) of <1.04 mmol/L, or receipt of specific
treatment for previously diagnosed low HDL-c; 4) systolic
blood pressure (SBP) of 130 mmHg and/or diastolic BP
(DBP) of 85 mmHg, or receipt of treatment for
previously diagnosed hypertension; 5) fasting plasma glucose
(FPG) of 6.1 mmol/L and/or 2 h postprandial glucose
(2hPG) of 7.8 mmol/L, or receipt of hypoglycemic
therapy for previously diagnosed type 2 diabetes.
Each study participant underwent coronary angiography
by the standard Judkins technique . All major
coronary arteries were imaged in at least two orthogonal
views. The angiographic analysis was performed by two
experienced cardiologists who were blinded to the
patients clinical information. Patients with 50% diameter
lumen stenosis in a major coronary artery (left main
coronary artery, left anterior descending artery or its first
diagonal branch, left circumflex artery or its first obtuse
marginal branch, and right coronary artery) were
classified as CAD.
Each study participant underwent complete physical
examination to obtain measurements of height, weight,
W, and BP. Body mass index (BMI) was calculated as:
[(weight in kg)/(height in m)2]. W was measured at the
midpoint between the inferior margin of 12th rib and
the iliac crest on the mid-axillary line.
Blood samples were collected after 10 h overnight fast and
stored at 80C until use. Study participants without a
history of diabetes received the standard 75 g oral glucose
tolerance test. All participants samples were assayed for
FPG and 2hPG by the standard glucose oxidase method.
Fasting insulin was measured via radioimmunoassay
(Linco Research, St. Charles, MO, USA) and insulin
resistance was estimated using the homeostasis model
assessment index (HOMA-IR) . Glycated hemoglobin
(HbA1c) level was measured by high-pressure liquid
chromatography (Bio-Rad Inc., Hercules, CA, USA). Serum
creatinine (SCr), uric acid (UA), and lipid profiles,
including TG, total cholesterol (TC), HDL-c and low-density
lipoprotein cholesterol (LDL-c), were assayed by standard
enzymatic procedures on an automated bioanalyzer
(7600020; Hitachi, Tokyo, Japan). The estimated
erular filtration rate (eGFR; expressed as mL/min/1.73 m )
was calculated according to the equation from the
Modification of Diet in Renal Disease (MDRD) study: [186 *
(SCr/88.4)-1.154 * (age)-0.203 * 0.742 (if female)] . Serum
C-reactive protein (CRP) was measured by a
particleenhanced immunonephelometry assay (Dade Behring Inc.,
Newark, NJ, USA). The 24 h urine albumin (24hALB)
concentration was determined by standard rate
nephelometry method. Sandwich enzyme immunoassays were used
to detect the levels of PEDF (BioVendor Laboratory
Medicine, Modrice, Czech Republic) and adiponectin (Li Ka
Shing, Faculty of Medicine, University of Hong Kong,
China). The inter- and intra-assay coefficients of variation
were <6.6% and <4.1% for PEDF, and <8.6% and <7.3% for
All statistical analyses were carried out with the
Statistical Package for Social Sciences software (version 16.0;
SPSS, Chicago, IL, USA). The clinical and biochemical
data of the subjects are presented as mean SD, except
for skewed variables that are presented as median with
interquartile range of 25-75%. Two-tailed tests and a 5%
level of significance were applied for all statistical
analyses. Intergroup comparisons of variables with normal
distribution were carried out by the unpaired Students
t-test; variables with non-normal distribution were
compared by the Wilcoxon rank-sum test. For dichotomous
or categorical variables, intergroup comparisons were
carried out by the Chi-squared (2) test. Spearmans
correlation was used to assess the relation between serum
PEDF and other clinical parameters. Multiple logistic
regression analysis was performed to identify factors that
were independently correlated with CAD; CAD was set
as the dependent variable and age, BMI, PEDF, CRP,
HOMA-IR, adiponectin, CAD family history, smoking
status, hypoglycemic therapy, anti-hypertensive therapy,
lipid-lowering therapy, components of MetS (including
central obesity, hyperglycemia, hypertension,
hypertriglyceridemia, and low HDL-c), as well as MetS itself
were assessed as the independent variables. Multivariate
stepwise regression analysis was used to further assess the
independent correlated clinical parameters of serum
PEDF; serum PEDF was set as the dependent variable and
age, BMI, W, glucose levels, BP, lipid profiles, HOMA-IR,
CRP, adiponectin, 24hALB, eGFR, UA, hypoglycemic,
anti-hypertensive, and lipid-lowering therapy
assessed as the independent variables.
Clinical characteristics of study participants
The overall average of serum PEDF was 10.9 (8.1, 13.8)
g/mL for the entire study population. The average
serum PEDF level was not significantly different between
the male and female patients (10.7 (8.0, 13.9) vs. 11.1
(8.4, 13.2) g/mL; P > 0.05).
Compared with non-CAD subjects, CAD patients
showed significantly higher age, 2hPG, HbA1c, and
SCr, but significantly lower level of HDL-c (all P < 0.05;
Table 1). The frequency of low HDL-c was significantly
higher in CAD patients (P < 0.05), while the frequency
of MetS and other components of MetS showed no
difference between the CAD and non-CAD groups (all
P > 0.05). In addition, the proportion of patients with
hypoglycemic therapy and lipid-lowering therapy was
significantly higher in the CAD group than in the
nonCAD group (both P < 0.05).
Association of serum PEDF levels with MetS
Serum PEDF levels were significantly higher in subjects
with MetS than in those without MetS (11.1 (8.2, 14.2) vs.
10.1(7.6, 12.4) g/mL; P < 0.05; Figure 1a). Spearmans
correlation analysis showed that serum PEDF was
positively correlated with hypertriglyceridemia (R = 0.213,
P < 0.001), but no significant correlation was observed
among other components of MetS.
Correlation of serum PEDF and CAD
As shown in Figure 1b, CAD patients had significantly
higher levels of serum PEDF than non-CAD subjects
(11.0 (8.1, 14.2) vs. 10.3 (8.1, 12.8) g/mL; P < 0.05).
Multivariate logistic regression analysis indicated that
age, PEDF and lipid-lowering therapy were
independently positively correlated with CAD (Table 2).
Influencing factors of serum PEDF levels
Table 3 shows the correlation analysis results for serum
PEDF with the various anthropometric variables and
clinical parameters. Serum PEDF was found to be
positively correlated with FPG, HbA1c, HOMA-IR, TG, CRP,
SCr and UA, and negatively correlated with eGFR.
Stepwise multivariate regression analysis indicated that TG,
CRP, eGFR, and hypoglycemic therapy were
independently correlated with serum PEDF (Table 4).
MetS is well recognized as an aggregate of
cardiometabolic risk factors subsequent cardiovascular disease
and type 2 diabetes mellitus [23,24], and the association
of PEDF with MetS and its components has been
Table 1 Characteristics of patients according to the presence or absence of CAD
verified in previous studies [12-14]. In a 10-year
prospective study, enhanced PEDF level was identified as an
independent predictor for the development of MetS in
men , which further affirmed the prediction effect of
PEDF on MetS. However, these studies focused solely on
subjects with CAD risk factors but no clinical evidence
of cardiovascular disease, which may have limited their
ability to extend this relation of serum PEDF with MetS
to the subsequent onset of cardiovascular disease. To
overcome this limitation, the present study enrolled
CAD and non-CAD subjects (~3:4 ratio) as well as MetS
and non-MetS subjects (~2:3 ratio) and still found that
serum PEDF level was significantly increased in the
MetS patient group. This finding agrees with previous
functional studies that indicated enhanced levels of
PEDF might exert a counteractive activity against
simultaneous enhancement of CAD risk factors [13,14].
In the current study of the broad panel of MetS
pathogenic components, PEDF was found to be significantly
positively correlated with hypertriglyceridemia, and TG
was identified as an independent influencing factor of
serum PEDF levels. Dyslipidemia is known to play an
important role in the development of atherosclerosis
and CAD. Specifically, long-term dyslipidemia has been
shown to cause physical injury to the vascular intima,
and the accompanying pro-inflammatory state of the
tissue promotes atherosclerosis and CAD. In clinical
studies, patients with elevated TG levels developed CAD
Figure 1 Comparison of serum PEDF levels between study participants with and without MetS (a) and CAD (b). The bars represent
median, 25th and 75th percentile of PEDF level.
more frequently than their counterparts with TG levels
in the normal range and TG has been identified as an
independent risk factor for coronary events [25,26]. In the
current study, TG was found to be strongly and
independently correlated with serum PEDF in patients with
CAD or at high risk of CAD. Moreover, these findings
also agree with the previous studies in patients without
CAD history [12,13]. It is possible that the enhanced
levels of serum PEDF in CAD or CAD-risk patients
reflect a response to hypertriglyceridemia, whereby the
body is attempting to correct the perturbance in the
lipid metabolism system . Intriguingly, we failed to
find any significant association of serum PEDF with the
other two principal components of MetS, central obesity
and hypertension. These negative findings may be
explained by the fact that a large portion of our subjects
had been receiving therapeutic treatments for
hyperglycemia, hypertension, or hyperlipidemia for long periods
prior to study participation; to account for this potential
confounding aspect, hypoglycemia therapy was entered
the equation in the multiple regression analysis of PEDF
levels. Body weight and W in subjects of this study
might have changed in response to a long-term influence
of medications; therefore, the relation of PEDF with
obesity might be masked by other determinants.
Substantial evidence exists to support the hypothesis
that PEDF plays a protective role against microangiopathy;
Table 2 Multivariate logistic regression analysis showing
factors independently associated with CAD
Variables of the original model included: age, BMI, PEDF, CRP, HOMA-IR,
adiponectin, central obesity, hyperglycemia, hypertension,
hypertriglyceridemia, low HDL-c, MetS, CAD family history, smoking,
hypoglycemic therapy, anti-hypertensive therapy, and lipid-lowering therapy.
a Logarithmically transformed before analysis.
moreover, PEDF has been proposed as a potential
protective factor against diabetic microvascular complications
[28-30]. Yet, few studies to date have investigated the
association of PEDF with macroangiopathy, as was done in the
current study which demonstrated for the first time that
serum PEDF was independently positively correlated with
CAD in a Chinese population. This finding contradicts a
previous study by Shiga et al., which showed no significant
correlation between PEDF and the presence of CAD in a
Japanese population ; however, this apparent
inconsistency may merely indicate the different inclusion subjects.
Fasting plasma glucose
2h postprandial glucose
Glycated hemoglobin A1c
Systolic blood pressure
Diastolic blood pressure
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
Estimated glomerular filtration rate
Table 4 Stepwise multivariate regression analysis of
serum PEDF levels
Variables of the original model included: age, BMI, W, FPG, 2hPG, HbA1c, SBP,
DBP, TC, TG, HDL-c, LDL-c, HOMA-IR, CRP, adiponectin, 24hALB, eGFR, UA,
hypoglycemic therapy, anti-hypertensive therapy, and lipid-lowering therapy.
a Logarithmically transformed before analysis.
Atherosclerosis, which is considered the pathological
basis of CAD, is a chronic inflammatory disorder .
Previous studies have shown that CRP was positively
correlated with PEDF, and suggested that this relation
may reflect the bodys attempt to suppress a detrimental
inflammatory reaction involving the endothelial cells
[14,33]. In our study, we found no difference in the CRP
levels of CAD and non-CAD patients, possibly because
the majority of those non-CAD patients actually
possessed many of the CAD risk factors and >60% of them
were MetS patients. Regardless, the multivariate stepwise
regression analysis performed for the study population
identified CRP as an independent influencing factor of
serum PEDF levels, and this finding agrees with the
proposed association of PEDF with chronic inflammation.
Furthermore, oxidative stress, which is elevated in
patients with metabolic disorder or CAD, could be one of
the triggers in the liver (an important source organ of
circulating PEDF), as hydrogen peroxide has been shown
to induce PEDF expression in human hepatocytes .
Given the fact that PEDF exerts anti-angiogenic,
antioxidative, anti-thrombotic, and anti-inflammatory
properties on vascular tissues, researchers have speculated
that PEDF levels might be elevated to counteract
generation of a pro-atherosclerotic environment induced by
vascular injuries [16,17]. Ueda et al. reported that PEDF
injection suppressed cardiac fibrosis, inhibited tissue
remodeling and improved cardiac function in a rat model
of acute myocardial infarction and suggested that PEDF
may be a novel therapeutic strategy for human acute
myocardial infarction . Since PEDF exerts a number
of protective effects on vascular and myocardial tissues,
elevated serum PEDF levels in CAD patients may also
play a counter-regulatory and protective role against
vascular damage caused by hypertriglyceridemia,
hyperglycemia, and chronic inflammation.
Moreover, Rychli et al. found that PEDF was
significantly associated with CAD (for trend, P = 0.037) and
correlated with rehospitalization for heart failure (HF)
worsening, with a more prominent risk increase
association in CAD patients; these previous findings further
support our current results. Rychli et al. also suggested
that PEDF was associated with chronic deterioration of
cardiomyopathy and played a role in the progression of
HF by inducing apoptosis of human cardiac myocytes
and fibroblasts . We believe that the elevated PEDF
observed in CAD patients occurs in response to vascular
injuries, chronic inflammation, and oxidative stress, and
that its function involves preventing CAD deterioration.
It has been reported that cardiovascular disease was
closely regulated through the signaling pathways of the
mammalian target of rapamycin (mTOR) which was
associated with endothelial cell survival and growth, as
well as cardiomyocyte proliferation . Wang et al.
confirmed the antiangiogenic property of PEDF and
firstly reported that insulin could down-regulate PEDF
expression, which at least partly depended on mTOR
kinase as the inhibitory effect of insulin on PEDF
expression would disappear when added the mTOR inhibitor
rapamycin . It is possible that PEDF would offer
exciting prospects for the development of new therapies
for cardiovascular disease.
Another physiological factor that was correlated with
the elevated PEDF levels in our study population was
eGFR (independently negatively correlated). This finding
is not surprising since renal filtration is known to affect
serum PEDF levels, and is in line with findings from
previous studies [15,31].
When interpreting the results from our present study, it
is important to consider some of the features of the
study design that may limit the generalizability of our
findings. Firstly, the cross-sectional design of the current
study precluded our ability to determine the cause-effect
relationship for PEDF and CAD. Secondly, the study
population was relatively small, and larger prospective
studies are necessary to confirm the role of PEDF in the
development of CAD. Moreover, the study population
was composed of individuals who were suspected of
CAD (admitted to hospital to undergo coronary
angiography) and most had several of the known risk factors of
CAD, which may have biased the results.
Nonetheless, the population of Chinese patients assessed
in this study demonstrated a significantly independent
correlation of serum PEDF with the presence of CAD.
Biologically, PEDF is capable of exerting a number of
protective effects under conditions of metabolic disorder,
and the mechanism fits with the observation of elevated
serum PEDF in patients with MetS and CAD. In
particular, elevated serum PEDF levels may represent a
counter-regulatory mechanism that acts as a protective
response against vascular damage and subsequent CAD.
Molecular targeting of PEDF might be a promising
therapeutic strategy for treatment of cardiometabolic
disorders and represent a useful predictive index for
treatment effectiveness. Further laboratory and clinical
studies are warranted to confirm the protective effect of
PEDF on cardiovascular disease and to assess its
potential as a therapeutic target.
BMI: Body mass index; BP: Blood pressure; CAD: Coronary artery disease;
CRP: C-reactive protein; eGFR: Estimated glomerular filtration rate;
FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin A1c; HDL-c:
Highdensity lipoprotein cholesterol; HOMA-IR: Homeostasis model
assessmentinsulin resistance; LDL-c: Low-density lipoprotein cholesterol; MetS: Metabolic
syndrome; PEDF: Pigment epithelium-derived factor; SCr: Serum creatinine;
TC: Total cholesterol; TG: Triglyceride; UA: Uric acid; W: Waist circumference;
2hPG: 2 h postprandial glucose; 24hALB: 24 h urine albumin.
YB and WJ designed the study. MZ, JN, and MG collected the data. FW
analyzed the data and drafted the manuscript. XP performed the PEDF
measurements. ZL and JH carried out the angiographic analysis. XM, YB, and
WJ revised the manuscript and contributed to discussion. All authors read
and approved the final manuscript.
This work was funded by 973 Program of China (2013CB530606), Project of
National Natural Science Foundation of China (81170788), National Key
Technology R&D Program of China (2012BAI02B03), Special Scientific
Research Fund of Medicine Sanitary (201002002), and Key Discipline of Public
Health of Shanghai (Epidemiology) (12GWZX0104).
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