# Antidiabetic Rosiglitazone Reduces Soluble Intercellular Adhesion Molecule-1 Level in Type 2 Diabetic Patients with Coronary Artery Disease

Authors: Guang Wang; Zhe Zhang; Jie Yu; Fuchun Zhang; Liyun He; Jinru Wei; Jieming Mao; Xian Wang
Journal: PPAR Research
 (2008)

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## Abstract

Background. We investigated the level of soluble adhesion molecules in diabetic patients and the effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone on plasma levels of adhesion molecules and an inflammation marker in type 2 diabetic patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Methods. A total of 116 diabetic patients with CAD who had undergone PCI were randomized to receive rosiglitazone (4 mg/d) or not for 6 months. Plasma levels of soluble intercellular adhesion molecules (sICAM-1) and P-selectin (sP-selectin) were measured on ELISA. Results. After 6-month rosiglitazone treatment, plasma levels of sICAM-1 were lower than baseline and control group levels (370.4 (332.4–421.9) pg/mL versus 423.5 (327.4–500.3) pg/mL and 404.6 (345.2–483.4) pg/mL, P<.001). In addition, plasma levels of C-reactive protein were significantly reduced from baseline levels. However, plasma level of sP-selectin was not significantly lowered with rosiglitazone treatment than with control treatment after 6-month follow-up. Conclusions. Rosiglitazone reduces chronic inflammatory responses and improves levels of markers of endothelial dysfunction in patients with diabetes and CAD. PPAR-γ agonist may have a beneficial effect on the vascular endothelium through its anti-inflammatory mechanism and may be useful as therapy in patients undergoing PCI.


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## Body

## 1. Introduction

Chronic  subclinical inflammation is
increasingly recognized as possibly contributing to the progression of
atherosclerosis and acute coronary syndromes. The formation and development of
atherosclerotic lesions involve accumulation of monocytes and T lymphocytes
[1]. The process of leukocyte adhesion and transendothelial migration is mediated
by cellular adhesion molecules, which are expressed on the endothelial surface
in response to many atherogenic stimuli [2]. Elevated plasma levels of soluble
adhesion molecules suggest a role in plaque instability and predict the
development of atherosclerosis and cardiovascular events in patients with
coronary artery disease (CAD) [3, 4]. In addition, several prospective studies
have demonstrated that plasma level of C-reactive protein (CRP) is an inflammatory
marker of cardiovascular disease. Chronic subclinical inflammation is part of
the insulin resistance syndrome [5]. Although the exact cause of
atherosclerosis is not clear, the improvement of metabolic disorders and
chronic   inflammation characterized by insulin resistance may significantly
decrease the risk of the disease.Peroxisome proliferator-activated
receptors (PPARs) are ligand-activated transcription factors that are a
subfamily of the nuclear receptor gene family. PPAR-γ plays a central role in
metabolism and is highly expressed in endothelial cells, vascular smooth muscle
cells, and macrophages [6]. The rosiglitazones are a class of pharmacological
compounds with high affinity to PPAR-γ. However, PPAR-γ agonists reduce plaque
inflammation by inhibiting the activation of several proinflammatory genes
responsible for plaque stability through decreasing the expression of adhesion
molecules [7, 8]. Troglitazone inhibits the interaction between leukocytes and endothelial
cells, decreases the expression of intercellular adhesion molecule-1 (ICAM-1)
in activated endothelial cells, and reduces monocytes homing to atherosclerotic
plaque [9, 10]. Furthermore, our
previous study demonstrated that PPAR-γ agonists significantly reduce
homocysteine-induced reactive oxygen species and secretion of monocyte chemoattractant protein-1 (MCP-1) in
monocytes [11]. Recently, we showed plasma levels of MCP-1 significantly decreased
with rosiglitazone treatment [12, 13]. However, whether PPAR-γ agonists can exert
a beneficial effect on soluble adhesion molecule levels to promote adhesion and
transendothelial migration of monocytes to endothelium in patients with
diabetes and CAD after percutaneous coronary intervention (PCI) is unknown.We aimed to investigate the level of soluble
adhesion molecules in diabetic patients and the effect of rosiglitazone on
plasma levels of adhesion molecules and an inflammation marker in type 2 diabetic
patients with CAD after PCI.


## 2. Methods

## 2.1. Subjects

Patients were selected from the
cardiovascular internal medicine practice at Peking University Third Hospital
between October 2002 and September 2005. We included 116 patients, aged 45 to 79
years old, with a diagnosis of CAD (>50% stenosis seen on angiography) and
type 2 diabetes mellitus. Patients with acute myocardial infarction during the
preceding 12 weeks, cardiac insufficiency, renal function impairment, liver
function impairment, systemic inflammatory disease, infectious disease, cancer,
or a serious illness that would affect their participation or patients under
insulin treatment were excluded.


## 2.2. Study Design

All 116 patients had undergone
angiography and percutaneous coronary intervention. The patients were divided
into two groups for treatment depending on sequence of patients recruited into the
study: control group (56 patients) and rosiglitazone group (60 patients), who
received 4 mg rosiglitazone daily for 6 months. One patient in the treatment
group withdrew during follow-up because of recruitment into another clinical
trial. Blood was sampled before and after angiography for 6 months for analysis
of clinical chemistry and inflammatory factors. Plasma was separated and stored
at−70°C for further analysis.All subjects gave their written,
informed consent. This study was approved by the Ethics Committee of the Health Science Center, Peking University.


## 2.3. Laboratory Measurements

Blood samples were drawn from an antecubital vein in the morning after overnight
fasting and collected into vacuum tubes containing EDTA to measure plasma lipid
levels. Total cholesterol (TC), high-density lipoprotein cholesterol
(HDL-C), low-density
lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels were
analyzed by colorimetric enzymatic assays with use of Auto-Analyzer
(HITACHI-7170). The measurements of fasting plasma glucose, fasting insulin,
and hemoglobin A1c were determined at
the Central Chemistry Laboratory, Peking University Third Hospital.Levels of CRP were measured
by the use of an enzyme-linked immunosorbent assay (ELISA) kit following the
manufacturers’ protocols (R&D systems, Minneapolis, Minn, USA). Plasma levels of soluble ICAM-1 (sICAM-1) and
P-selectin (sP-selectin) were measured by ELISA (GeneMay,
Inc., San Diego, Calif, USA)
according to the manufacturer’s protocols. The estimate of homeostasis model
assessment-insulin resistance (HOMA-IR) was as follows: IR = (fasting insulin (μU/mL) ×  fasting glucose (mmol/L))/22.5.


## 2.4. Statistical Analysis

Differences between groups in levels of glucose,
TC, LDL-C, HDL-C were
analyzed by Student’st test. Values for continuous variables are expressed as means ± SD. Plasma levels of soluble ICAM-1 are
given as medians and ranges and were assessed
by non-parametric tests (Mann Whitney U-test). Proportions were analyzed by use of the chisquare test. A value of P<.05 (two-tailed) was considered
statistically significant.


## 3. Results

## 3.1. Clinical Characteristics of Patients

The characteristics of patients are summarized in Table1. The control and rosiglitazone groups did not differ significantly in
baseline demographics; risk factors for atherosclerosis; prevalence of smoking, hypertension, hyperlipidemia, and use of other medications; as well as laboratory
values or plasma levels of inflammatory factors. The two groups did not differ in medical
therapy during 6-month follow-up other than use of rosiglitazone or in diabetic
duration or complications.Table 1
Baseline clinical characteristics of patients
with diabetes and coronary artery disease after percutaneous coronary
intervention.
Controln=56Rosiglitazonen=60CharacterAge, years63.20±7.5061.60±7.60Body mass index25.50±2.7026.10±2.60Sex (M/F)45/1049/11Risk factors, no.Hyperlipidemia2426Hypertension4142Smoking2328Parameters (levels)Cholesterol, mmol/L4.80±0.574.85±0.48High-density
lipoprotein,  mmol/L1.02±0.151.04±0.12Low-density lipoprotein,  mmol/L2.87±0.632.93±0.78Triglycerides, mmol/L2.01±0.701.99±0.63Fasting insulin,  mμ/L11.40±1.7213.10±1.84Fasting plasma glucose, (mmol/L)7.20±1.357.10±1.42HbA1c, %7.23±0.687.15±0.72HOMA-IR3.85±0.384.12±0.38CRP, mg/dL1.84±0.211.66±0.23sICAM-1, ng/mL407.1 (344.3–476.1)423.5 (327.4–421.9)sP-selectin,
ng/mL172.6 (123.3–223.3)182.5
(127.2–212.9)MedicationAspirin5560B-blocker5153Lipid-lowering drugs5158Nitrates2423Ca-Antagonists77ACE inhibitors4343Other antidiabetic drugs3435Biguanides2224Acarbose88Sulfonylureas45HOMA-IR: homeostasis-model-assessment insulin resistance; CRP:
C-reactive protein; sICAM-1: soluble intercellular adhesion molecule-1; HbA1c: hemoglobin A1c; sP-selectin: soluble P selectin. Data are means ±
SD or medians and ranges.


## 3.2. Effects of Rosiglitazone Treatment on Metabolic Parameters

After 6-month rosiglitazone
treatment, the level of hemoglobin A1c was significantly decreased in the rosiglitazone group as compared with
baseline and control levels (Figure1(a); 6.14±0.68% versus 7.15±0.72% and 6.67±0.65%, P<.001). Similarly, rosiglitazone significantly decreased
the level of fasting plasma insulin and glucose as compared with baseline and
control levels (7.60±1.15 mmol/L versus 13.10±1.84 mmol/L and 11.10±1.60 mmol/L, P<.001; 6.04±1.15 mmol/L versus 7.10±1.42 mmol/L and 7.08±1.23 mmol/L, P<.001; Figures 1(b)-1(c)). HOMA-IR levels were significantly
decreased after 6-month treatment (2.9±0.32 versus 4.12±0.38 and 3.92±0.36, P<.001, Figure 1(d)), as expected. However, hemoglobin A1c and fasting plasma glucose levels were
not significantly different from the control group at 6-month follow-up (Table 1). In addition, plasma levels of TC, HDL-C, LDL-C were significantly decreased
with rosiglitazone treatment as compared with baseline levels,
with no significant
difference between the rosiglitazone and control group at 6-month follow-up
(Table 2).Table 2
Metabolic features of patients before and 6
months after rosiglitazone treatment. Values are mean ± SD.
Metabolic parametersControl
group (n=56)Rosiglitazone
group (n=60)Baselineafter 6 monthsBaselineafter 6 monthsTotal cholesterol, mmol/L4.80±0.574.33±0.51*4.85±0.484.27±0.42#High-density
lipoprotein, mmol/L1.02±0.151.26±0.11#1.04±0.121.35±0.15#Low-density
lipoprotein, mmol/L2.87±0.632.67±0.552.93±0.782.53±0.73*Triglycerides, mmol/L2.01±0.701.75±0.611.99±0.631.62±0.62Body mass index25.50±2.725.37±2.3426.17±2.6026.49±2.11*P<.05
compared to baseline;#P<.01 compared to baseline.(a) Changes in levels of hemoglobin A1c, (b) fasting plasma insulin, and
(c) glucose, as well as (d) HOMA-IR, with 6-month rosiglitazone
treatment. Data are means
± SD. Control group,n=56; rosiglitazone (RSG) group, n=60. HbA1c: hemoglobin A1c;
HOMA-IR: homeostasis
model assessment-insulin resistance.
(a)(b)(c)(d)Weight gain can be a major
drawback in treatment with a PPAR-γ agonist.
Body weight was increased but not significantly from the baseline and control levels
after 6-month rosiglitazone treatment (Table 2).


## 3.3. Rosiglitazone Effect on Plasma Levels of Inflammatory Markers sICAM-1, sP-Selectin, and CRP

Plasma
sICAM-1 levels were significantly decreased in the rosiglitazone group compared with baseline and control levels after 6-month
treatment (370.4
(332.4 to 421.9) pg/mL versus 423.5 (327.4 to 500.3) pg/mL and
404.6 (345.2 to 483.4) pg/mL,P<.001) (Figure 2(a)). Plasma sP-selectin
levels were
not significantly lower in the rosiglitazone group than at baseline or in the control group after 6-month
treatment (170.2 (119.2 to 251.9) pg/mL versus 182.5 (127.2 to 212.9) pg/mL and
175.2 (119.2 to 251.8) pg/mL, P>.05). In addition, plasma levels of sICAM-1 and
sP-selectin did not differ from control levels before and after 6-month
treatment (Figures 2(a)-2(b)).Effect of rosiglitazone
treatment on plasma levels of soluble ICAM-1 (sICAM-1) (a) and P-selectin
(sP-selectin) (b) in patients with diabetes and coronary artery disease after percutaneous coronary intervention.
Data are medians and ranges. Control group,n=56; rosiglitazone (RSG) group, n=60.
(a)(b)Plasma
CRP levels in the rosiglitazone
group were significantly reduced from1.66±0.23 to 0.88±0.21 mg/L after 6-month treatment (Figure 3) and were significantly lower than in controls after
6-month treatment (mean 0.88±0.21 versus 1.69±0.25 mg/L, P<.0001). CRP
levels in the control group did
not differ from baseline levels after 6-month follow-up.Figure 3
Effect of rosiglitazone
treatment on plasma levels of C-reactive protein (CRP) in patients with
diabetes and coronary artery disease after percutaneous coronary intervention.
Data are means ± SD. Control group,n=56; rosiglitazone (RSG)
group, n=60.


## 3.4. Rosiglitazone Effect on Coronary Events during 6-Month Follow-Up

Eleven patients in the rosiglitazone group had coronary events
(recurrent unstable angina in 8, percutaneous translational coronary
angioplasty in 2, and coronary artery bypass grafting in 1) versus 14 patients
in the control  group (recurrent unstable angina in 7, percutaneous  translational
coronary angioplasty in 2, sudden death in 1,  and coronary artery bypass grafting
in 4) at 6-month follow-up,  with no significant difference between the two
groups.


## 4. Discussion

Chronic low-grade inflammation is associated
with cardiovascular events in patients with CAD or diabetes. Endothelial cell
expression of adhesion molecules and the adhesion of leukocytes to the endothelium
play a key role in the development of atherosclerotic plaque and plaque
instability. Endothelial function may be assessed by measuring plasma levels of
endothelial products such as soluble adhesion molecules. Our study demonstrates
that 6-month treatment with the PPAR-γ rosiglitazone treatment significantly
improved metabolic parameters, including insulin resistance in patients with
diabetes and CAD. In addition, rosiglitazone treatment significantly decreased
the plasma levels of sICAM-1 and inflammatory marker CRP as compared with
baseline and control levels.Atherosclerosis is characterized by the
recruitment of monocytes
and lymphocytes to the artery wall. A number of studies have determined the
important role
of adhesion molecules in
atherosclerotic plaque formation [2, 3]. P-selectin is responsible in part for the adhesion of
certain leukocytes and platelets to the endothelium. Animal models have also
shown the important role of P-selectin in the process of atherogenesis. For
example, increased P-selectin expression has been demonstrated in active
atherosclerotic plaques. Increased levels of soluble P-selectin in plasma have also
been demonstrated in CAD [14]. Several studies have demonstrated plasma levels
of CRP positively associated with risk of cardiovascular disease and clinical
events. CRP may exert a direct effect in promoting the progression of
atherosclerosis and plaque instability [15]. Rosiglitazone
significantly reduces levels of markers of endothelial cell activation and CRP in
CAD patients without diabetes; potential mechanisms include insulin
sensitization and modification of inflammation within the vessel wall [16].PPAR-γ is expressed in most cells of
the vascular wall and atherosclerotic lesions [17, 18]. The binding of monocytes
to adhesion molecules expressed on the surface of endothelial cells and their
infiltration into the subendothelial space may be reduced by PPARγ agonists.
The PPAR-γ agonist troglitazone inhibits the interaction between leukocyte
endothelial cells and decreases the expression of vascular cell adhesion
molecule-1 (VCAM-1) and ICAM-1 in activated endothelial cells and reduces monocyte homing to atherosclerotic
plaque [9, 10]. In recent years, PPAR-γ agonists have been increasingly used to
treat patients with type 2 diabetes mellitus. Such treatment is aimed at
reducing the incidence of vascular complications, including myocardial
infarction and restenosis after PCI. Animal studies have shown that
troglitazone prevents neointimal formation after endothelial balloon injury in
rats [18]. A recent study showed that pioglitazone suppresses in-stent
restenosis by limiting local inflammatory pathways in atherosclerotic rabbits
[19]. Clinical studies have shown that pioglitazone reduces neointimal volume
after coronary stent implantation in nondiabetic patients [20]. As well, rosiglitazone improves diabetes compensation, significantly
reducing VCAM-1 level, and E-selectin concentrations in patients with diabetes
[21]. Plasma concentrations of CRP and E-selectin were shown to
decrease significantly after rosiglitazone treatment for 3 months in diabetic
patients, although concentrations of ICAM-1 and VCAM-1 did not decrease [22]. Recently, we showed that plasma levels of MCP-1 and hyperresponsiveness of low-dose
lipopolysaccharide-induced MCP-1 secretion from monocytes were significantly
reduced by rosiglitazone treatment in patients with type 2 diabetes and serious
vascular disease [15]. Therapy with rosiglitazone decreased the serum levels of MCP-1 in obese type-2 diabetic patients
[23]. As well, pioglitazone
reduces the levels of ICAM-1 and VCAM-1 in obese patients without diabetes, without affecting soluble E-selectin levels [24].In the present study, we demonstrated
further that rosiglitazone significantly decreased plasma sICAM-1 level in diabetic
patients with CAD after PCI. However, plasma levels of sP-selectin were not
changed significantly by rosiglitazone treatment. Given that chronic subclinical
inflammation is important in atherosclerosis and restenosis after PCI,
inhibiting the proinflammatory adhesion molecule sICAM-1 and CRP levels by rosiglitazone,
might have potentially beneficial effects in type 2 diabetic patients with CAD.Patients with insulin resistance also
have enhanced risk of atherosclerosis. Chronic inflammation may play an
important role in the development of insulin resistance and endothelial
dysfunction. PPAR-γ agonists may modulate insulin action, which results in
change in expression of a number of genes involved in glucose level, lipid
metabolism, and inflammation. These changes are associated with the reversal of
many components of the insulin resistance syndrome. Hence, in our study, the reduction in inflammatory marker levels
may be due to a collective effect of rosiglitazone and better metabolic control.
Recently, Ryan et al. [24] reported that pioglitazone treatment improved
insulin resistance and endothelial function and reduced arterial stiffness in
obese men. Our results, together with previous ones, show that fasting plasma
glucose, insulin, and hemoglobin A1c levels, as well as HOMA-IR, are all decreased significantly by 6-month rosiglitazone
treatment. Thus, the reversal of the insulin resistance syndrome with
rosiglitazone is associated with improved cardiovascular risk factors in
patients with diabetes and CAD after PCI.In conclusion, antidiabetic rosiglitazone
therapy may play an important role in protecting endothelial function by
normalizing the metabolic disorders of diabetes mellitus and depressing the
chronic inflammatory response of the vascular wall, eventually reducing the
occurrence of coronary events and restenosis after PCI in type 2 diabetic
patients with CAD.



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