Vol.2, No.3, 272-278 (2010)
doi:10.4236/health.2010.23039
Copyright © 2010 SciRes Openly accessible at http://www.scirp.org/journal/HEALTH/
Health
Higher expression of connexin 40 in human atrial tissue
of patients with type 2 diabetes who have undergone a
coronary artery bypass graft surgery
Pascal Daleau1,2, Geneviève Comeau1, Dominique Fournier1, Dany Patoine1, Patrick Mathieu1,3,
Paul Poirier1,2
1Quebec Heart and Lungs Institute, Laval Hospital Research Centre, Quebec, Canada;
2Faculty of Pharmacy, Laval University, Quebec, Canada
3Faculty of Medicine, Laval University, Quebec, Canada
Received 21 November 2009; revised 13 January 2010; accepted 16 January 2010.
ABSTRACT
Background: Although cardiac-related mortality
rates are declining for the general population in
the United States, this is not the case for pa-
tients with diabetes. Diabetes is a significant
independent predictor of atrial fibrillation (AF),
the most common cardiac rhythm disturbance
responsible for substantial morbidity and mortality.
Objectives: This research was designed to
evaluate properties of the atrial tissue between
patients with and without type 2 diabetes. Heart
rate variability (HRV) indices were calculated
and expression of Kv1.5, connexin 43 (Cx43),
and 40 (Cx40) were compared. Methods: Pa-
tients undergoing a CABG were enrolled: 10
with type 2 diabetes and 8 without diabetes,
paired for age, gender and co-morbidities such
as hypertension and dyslipidemia. All patients
showed normal ejection fraction. A sample of
right auricular appendix was taken during CABG
and Kv1.5, Cx40 and Cx43 protein contents were
determined by western blotting and normalized
to α-tubulin level. Results: No HRV difference
was found between patients with and without
diabetes. Cx43 and Kv1.5 levels were unaffected
by diabetes (p=0.20 and 0.07, respectively) whe-
reas Cx40 content was significantly increased
by 55% (p=0.02). Levels of Cx43 phosphorylated
and non-phosphorylated forms were non-sig-
nificantly decreased in patients with diabetes.
Conclusion: Patients with type 2 diabetes had
higher expression of Cx40 in the right auricular
appendix tissue. In light of other studies having
demonstrated a link between AF and Cx40 ex-
pression, it is possible that higher prevalence of
AF in patients with diabetes is explained, at least
partially, by differential expression of gap-junc-
tion proteins.
Keywords: Diabetes; Gap Junctions; Atrial Tissue;
Atrial Fibrillation
1. INTRODUCTION
The prevalence of diabetes is steadily increasing in west-
ernized societies as well as in developing countries. Al-
though the overall cardiac-related mortality rate has been
declining for the general population in the United States,
this is not the case for patients with diabetes [1]. Of par-
ticular significance, diabetes is a risk factor for different
heart-related conditions such as coronary artery disease,
heart failure, aortic stenosis and arrhythmias [2].
Atrial fibrillation (AF) is the most common arrhyth-
mia and is responsible for substantial morbidity and
mortality [3]. In the Framingham study, systemic hyper-
tension and diabetes were found to be independent pre-
dictors of AF [4]. For men and women, respectively,
diabetes increased by 1.4 and 1.6 fold the risk of devel-
oping AF. The risk of developing AF correlates with
atrial dilatation, and the presence of left ventricular dia-
stolic dysfunction [5]. Since AF occurs as an ongoing
process over time, subtle atrial abnormalities may pre-
cede overt atrial dilatation and contractile dysfunction
[5-7]. These could be linked to alterations in electro-
physiological properties predisposing to AF.
In animal models (mostly streptozotocin-induced dia-
betes models), diabetes mellitus is responsible for car-
diac arrhythmias, probably caused by an excessive
lengthening of the cardiac action potential [8]. Several
changes in ionic currents have been described in car-
diomyocytes isolated from animal models of diabetes,
principally a decrease in the transient repolarizing potas-
sium current Ito [8,9]. This effect could possibly be par-
tially mediated by impaired sympathetic nervous system

P. Daleau et al. / HEALTH 2 (2010) 271-277
Copyright © 2010 SciRes Openly accessible at http://www.scirp.org/journal/HEALTH/
273
activity [10] or by oxidative stress-induced alteration in
the glutathione redox state [11].
It should be pointed out that a reduction in Vmax, [12]
the maximum speed of the rising phase of the action
potential, and a prolongation of the QRS complex [13,
14] have been associated with diabetes. Changes in the
intercellular electrical coupling through gap junctions
could be involved in this effect. Indeed, it was demon-
strated that elevated glucose concentrations inhibit gap
junction intercellular communication and reduced con-
nexin (Cx) expression in a variety of cells including
vascular smooth muscle cells, endothelial cells, and
retinal microvessels. It has been proposed that high glu-
cose concentration interfered with gap junction through
the activation of protein kinase C [15-18]. In addition, it
has been reported in rat model of diabetes that a
down-regulation of Cx43 occurred and is associated with
a compensatory over-expression of other Cxs [19,20].
However, direct alteration of gap junctions by diabetes
were never assessed in human cardiomyocytes.
The purpose of this study was to evaluate properties
of the atrial tissue between patients with and without
type 2 diabetes. Heart rate variability (HRV) indices
were calculated to evaluate the potential influence of the
cardiac autonomic nervous system. Expression levels of
Kv1.5 (underlying IKur), connexin 43 (Cx43), and 40
(Cx40) were compared between patients with and with-
out type 2 diabetes.
2. RESEARCH DESIGN AND METHODS
2.1. Study Design
Ten subjects with type 2 diabetes and 8 subjects without
diabetes undergoing a coronary artery bypass grafting
surgery (CABG) were enrolled in this study. Patients in
sinus rhythm aged between 35 and 70 were included.
Patients with and without type 2 diabetes were paired for
age, gender, co-morbidities such as hypertension and
dyslipidemia. All patients had to show normal ejection
fraction. Exclusion criteria were: 1) previous history of
supraventricular arrhythmia, 2) significant hepatic or
renal dysfunction (creatinine >150 mmol/L), 3) signifi-
cant pulmonary or thyroid disease, 4) any connective
tissue disease or history of malignancy, 5) episode of
recent heart failure, 6) acute coronary syndrome within
the last 3 months and, 7) smoking within the previous 3
months. The present study was approved by the local
ethical committee of Laval Hospital.
A sample of right auricular appendix was taken at the
beginning of the CABG procedure, and immediately
placed in an oxygenated Tyrode solution (in mM: NaCl
137, KCl 5.4, CaCl2 1.8, MgCl2 1, NaHCO3 12,
NaH2PO4 0.4, glucose 5.6) at 4℃. The tissue was sub-
sequently immersed in liquid nitrogen and stored at -80
℃ for western analyses.
2.2. Heart Rate Variability
Heart rate variability (HRV) was derived from a 24-hour
Holter monitoring system (Marquette Electronics Inc.,
Milwaukee, WI) in all subjects during normal daily life
activity. HRV derived from 24-hour ambulatory moni-
toring is reproducible and free of placebo effect [21].
Using frequency domains, power in the low frequency
(LF, 0.04-0.15 Hz) that is an index of both sympathetic
and parasympathetic activity, and high frequency (HF,
0.15-0.4 Hz) that is an index of solely parasympathetic
activity, were calculated. LF/HF ratio is the power in
low frequency divided by the power in high frequency.
Using time domains, the standard deviation of the RR
intervals (SDNN), the square root of the mean squared
differences of successive RR intervals (rMSSD) and the
standard deviation of the average RR intervals calculated
over 5-min periods (SDANN) were determined. pNN50
is the proportion of interval differences of successive
NN intervals greater than 50 ms. NN intervals are the
normal-to-normal intervals that include all intervals be-
tween adjacent QRS complexes resulting from sinus
node depolarizations in the entire 24-hour ECG re-
cording as previously reported [7].
2.3. Protein Isolation and Western Blot
Analysis [22,23]
Total protein content was determined with bovine serum
albumin as standard and subsequently separated with an
8% denaturing-PAGE. Proteins transferred to Immobilon
PVDF membranes were incubated with antibodies for
Kv1.5 [Alomone Labs], Cx40 [Chemicon Int.] (poly-
clonal, raised in rabbit) and Cx43 [Chemicon Int.]
(monoclonal, mouse). Epitopes are residues 513-602 of
mouse Kv1.5, gap junction alpha-5 protein of mouse
connexin 40 [CxA-5], and residues 252-270 of native
sequence from rat cardiac connexin 43, respectively. All
primary antibodies specific for these 3 proteins were
diluted in TBS-Tween 1:200. Membranes were respec-
tively incubated with secondary antibodies (1:10000 and
1:5000, anti-rabbit [Cedarlane]; 1:100000, anti-mouse
[Chemicon Int.]), conjugated with peroxidase. An ECL
detection kit [Millipore] was used to reveal the anti-
gen-antibody for subsequent densitometric analysis.
Kv1.5, Cx43 and Cx40 protein levels were normalized to
α-tubulin level (1:250, polyclonal, raised in rabbit, Ab-
cam).
2.4. Statistical Analysis
Patient characteristics, Holter and blood chemistry pa-
rameters are reported as mean ± standard deviation
unless otherwise specified (S.D.). Densitometry values
are expressed as mean ± S.E.M. Comparisons between

P. Daleau et al. / HEALTH 2 (2010) 271-277
Copyright © 2010 SciRes Openly accessible at http://www.scirp.org/journal/HEALTH/
274
groups were performed using an unpaired Student’s
t-test and a p value<0.05 was considered significant.
3. RESULTS
There was no difference in age, body mass index (BMI)
and left ventricular ejection fraction between groups
(Table 1). As expected, fasting glucose level was sig-
nificantly higher in patients with diabetes (Table 1).
There were no differences in the lipid profile between
groups. Also, drug regimen was comparable between
groups except for the use of hypoglycaemic agents in
patients with diabetes (Table 2). Results from the
24-hour Holter analysis, showed no significant differ-
ence in the indices assessed (LF, HF, LF/HF ratio,
SDANN, rMSSD, pNN50, mean NN, SDNN) between
patients with and without diabetes.
Densitometric analysis showed that Cx43 levels
(normalized with α-tubulin and tested in triplicate) were
unaffected by diabetes (Figure 1, p = 0.20). When com-
pared to control subjects, patients with diabetes had a
tendency of having higher expression of Kv1.5 (Figure
3, p=0.07), whereas Cx40 content was significantly in-
creased by 55% (Figure 2, p=0.02). We also assessed
expression levels of phosphorylated forms of Cx43. In
patients with diabetes, expression levels of the two
phosphoisoforms of Cx43 (P2 and P1) were decreased to
71% and 64% of control values respectively. The
non-phosphorylated form of Cx43 (P0) decreased to
79% of control values. However, these differences were
Figure 1. Representative Western blots of right auricular ap-
pendix Cx43 protein level. P0 represents the nonphosphory-
lated form, while P1 and P2 represent two phosphoisophorms
of Cx43. The lower panel shows densitometry of Cx43 nor-
malized to α-tubulin (expressed as % of tubulin densitometry)
in diabetes and control patients (one Control was lacking due
to limited tissue availability). Data are means ± s.e.m.
Figure 2. Representative Western blots of right auricu-
lar appendix Cx40 protein level. The lower panel shows
densitometry of Cx40 normalized to α-tubulin (ex-
pressed as % of tubulin densitometry) in diabetes and
control patients. Data are means ± s.e.m.; * P
＜ 0.05.
Figure 3. Representative Western blots of right auricular
appendix Kv1.5 protein level. For tubulin, only the lower
band was considered for densitometric analysis; the upper
band was due to a non-specific binding of the Kv1.5 anti-
body. The lower panel shows densitometry of Kv1.5 nor-
malized to α-tubulin (expressed as % of tubulin densitometry)
in diabetes and control patients. Data are means ± s.e.m.
not significant for all isoforms (p = 0.46, 0.21 and 0.23
respectively for P0, P1 and P2).
Among patients with diabetes, 50% (5/10) developed
new onset of postoperative AF significant enough (epi-
sodes longer than 2h or recurrent episodes of AF) to
require pharmacological treatment compared to 25%
(2/8) in the control group (p = 0.27).

P. Daleau et al. / HEALTH 2 (2010) 271-277
Copyright © 2010 SciRes http://www.scirp.org/journal/HEALTH/Openly accessible at
275
Table 1. Patient characteristics.
Diabetes
(n=10)
Controls
(n=8)
P
value
Age (years)
BMI (kg/m2)
EF (%)
Men/Women
61.5 ± 13.1
34.1 ± 7.5
57.3 ± 7.1
7/3
68.4 ± 6.7
29.5 ± 4.4
63.4 ± 8.7
7/1
0.197
0.198
0.065
0.815
Blood analysis:
Glucose (mmol/L)
HbA1c (%)
Apo B (g/L)
7.2 ± 1.6
7.1 ± 1.0
0.71 ± 0.18
5.2 ± 0.6
-
0.86 ± 0.21
0.003
-
0.148
Lipid profile:
Total cholesterol (mmol/L)
Triglycerides (mmol/L)
HDL cholesterol (mmol/L)
LDL cholesterol (mmol/L)
Total-C/HDL-C
3.54 ± 0.62
1.72 ± 0.87
1.11 ± 0.14
1.65 ± 0.48
3.20 ± 0.58
4.04 ± 0.81
1.82 ± 0.99
1.18 ± 0.27
2.03 ± 0.50
3.57 ± 1.08
0.160
0.756
0.657
0.120
0.372
BMI = Body mass index; EF = Ejection fraction
Table 2. Co-morbidities and drug regimen in both groups.
Diabetes
% (n)
(n=10)
Controls
% (n)
(n=8)
P value
History
Hypertension
Dyslipidemia
Smoking
70 (7)
70 (7)
10 (1)
62.5 (5)
75 (6)
37.5 (3)
0.107
1.000
1.000
Rx Classes
Nitroglycerin
β-blockers
CCB
ACEI
ARB
α1 inhibitors
ASA
Diuretics
Statins
Fibrates
Oral hypoglycemic agents
Benzodiazepine
Antidepressants
40 (4)
90 (9)
50 (5)
30 (3)
60 (6)
10 (1)
90 (9)
40 (4)
90 (9)
-
100 (10)
10 (1)
10 (1)
50 (4)
87.5 (7)
50 (4)
-
12.5 (1)
12.5 (1)
87.5 (7)
-
62.5 (5)
12.5 (1)
-
25 (2)
-
0.143
1.000
1.000
-
1.000
1.000
0.125
-
0.375
-
-
1.000
-
4. DISCUSSION
This study assessed the effects of type 2 diabetes on the
expressions of connexins and Kv1.5 in the human heart.
The most important finding of this work is that patients
with type 2 diabetes had significantly higher expression
of Cx40 in the right auricular appendix tissue. Apart
from the diabetic status, the 2 groups were well matched
in terms of age and risk factors, implying that the ob-
served modulation of connexin is likely to reflect the
effect of diabetes per se.
4.1. Expression of Connexins and
Modulation by Diabetes
Assessment of protein content revealed that when com-
pared to control patients, the level of Cx40 in the right
auricular appendix specimens was increased by 55 % in
individuals having type 2 diabetes. Similarly, a recent
study in rats with streptozotocin-induced diabetes has
shown that expression of Cx40 was increased in retinal
microvessels [18]. Although not statistically significant,
we also observed a trend toward a decreased expression
of Cx43 in the right auricular appendix tissues of pa-

P. Daleau et al. / HEALTH 2 (2010) 271-277
Copyright © 2010 SciRes Openly accessible at http://www.scirp.org/journal/HEALTH/
276
tients with type 2 diabetes. All isoforms of Cx43 (the
two phosphoisoforms and the non-phosphorylated form),
were diminished, although non-significantly. It should
be emphasized that in diabetic animal models a reduc-
tion in the expression of Cx43 has been documented in
several tissues [17,24,25], including the heart [18,26],
though exceptions also exist [27,28].
In one study, while a down-regulation of Cx43 was
demonstrated in retinal microvessels of diabetic rats, an
over-expression of Cx40 and Cx45 were found [18].
Thus, it seems possible that a down-regulation of one
type of connexin is offset by the increased production of
another type of gap junction protein. In the same line, a
recent study analyzing the expression of connexins in the
bladder of diabetic rat reported a lower amount of Cx43
isoform and higher expression of Cx32 and 26 [17].
However, it has been stressed that the function of one
type of connexin cannot necessarily be restored by the
presence of another but different member of the con-
nexin family [29]. Hence, this ‘replacement’ hypothesis
certainly deserves more investigations.
4.2. Atrial Fibrillation, Connexins and K+
Channels
Diabetes has been reported as a strong and independent
risk factor for the development of AF [30,31]. Of note,
episodes of postoperative AF have been associated to a
higher expression Cx40 in the right auricular appendix
obtained from patients undergoing cardiac surgery [32,
33,34,35]. It is likely that the relative abundance of Cx43
and Cx40 plays an important role in the atrial impulse
propagation, and whereby dominance of Cx40 decreases
local propagation velocity [36]. Therefore, the modula-
tion of Cx40 expression by the diabetic environment
could lead to micro-heterogeneities of electrical conduc-
tion pattern, promoting by this way episodes of AF.
In different studies with experimental animal models, the
activity of several cardiac potassium currents, such as Ito, IK
and Iss, are modulated by diabetes and are possibly involved
in the development and/or maintenance of AF [37,38,39].
However, the present results in human right auricular ap-
pendix tissue show that Kv1.5 expression remains un-
changed in patients with diabetes, suggesting that IKur is not
affected. Nevertheless, one cannot exclude a direct modula-
tion of this current by glucose and/or insulin levels.
4.3. Clinical Implications
AF is the most frequent arrhythmia and has been linked
to aging as well as to diabetes. While atrial remodeling
is undoubtedly an important process participating to the
development and the maintenance of AF, an electro-
physiological substrate is actively involved in the genera-
tion of arrhythmia. In this regard, the dispersion of atrial
refractoriness and the ensuing development of multiple
reentry wavelets are likely to be important underlying
mechanisms pertaining to AF. In this study, the finding of
a significant modulation of Cx40 in patients with diabetes
may partly explain the well-documented association be-
tween diabetes and AF. By which mechanism diabetes
contributes to increase Cx40 expression in atrial tissue is
still unknown, but it is possible that inflammatory and/or
oxidative stress pathways [40, 41], which are incidentally
activated in subjects with diabetes, may contribute to
modify the amount of connexins in atrial cardiomyocytes.
4.4. Limitations
Insofar patients in the present study had significant
coronary artery disease and other co-morbidities, the
present findings cannot be inferred to the overall spec-
trum of patients with diabetes. Particularly, pre-diabetic
subjects with glucose intolerance were not studied and
may have given further insights as to whether the ob-
served modifications may occur at an earlier stage. In
addition, the size of the left atria, which represent atrial
remodeling, was not documented in the present study.
However, the effect of atrial remodeling, a possible
confounding variable, was minimized by having selected
a cohort of patients without significant valve disease, a
normal ejection fraction, and in sinus rhythm.
4.5. Conclusions
In conclusion, we found an up-regulation of Cx40 pro-
tein content in right auricular appendix tissue from pa-
tients with type 2 diabetes. In light of other studies hav-
ing demonstrated a link between AF and Cx40 expres-
sion, it is possible that higher prevalence of AF in pa-
tients with diabetes is explained, at least partially, by
differential expression of gap-junction proteins. Albeit
further studies are still needed to understand the full im-
plication of Cx40 in AF, this study casts some light on a
potentially important process occurring in individuals
with diabetes, and may open-up new therapeutic and/or
research vistas in order to treat and/or prevent AF in this
at-risk population.
5. ACKNOWLEDGEMENTS
Drs Paul Poirier and Patrick Mathieu are research scholars from the
Fonds de la Recherche en Santé du Québec. This work was supported
by operating grants from the Quebec Heart Institute (Drs Paul Poirier
and Pascal Daleau) and the Heart and Stroke Foundation of Quebec
(Dr Pascal Daleau).
REFERENCES
[1] Gu, K., Cowie, C.C. and Harris, M.I. (1999) Diabetes
and decline in heart disease mortality in US adults. Jour-
nal of the American Medical association, 281, 1291-
1297.

P. Daleau et al. / HEALTH 2 (2010) 271-277
Copyright © 2010 SciRes Openly accessible at http://www.scirp.org/journal/HEALTH/
277
[2] Grundy, S.M., Benjamin, I.J., Burke, G.L., Chait, A.,
Eckel, R.H., Howard, B.V., Mitch, W., Smith, S.C.Jr.
and Sowers, J.R. (1999) Diabetes and cardiovascular
disease: a statement for healthcare professionals from the
American Heart Association. Circulation, 100, 1134-
1146.
[3] Fuster, V., Ryden, L.E., Cannom, D.S., Crijns, H.J., Cur-
tis, A.B., Ellenbogen, K.A., Halperin, J.L., Le Heuzey,
J.-Y., Kay, G.N., Lowe, J.E., Olsson, S.B., Prystowsky,
E.N., Tamargo, J.L. and Wann, S. (2006) ACC/AHA
Task Force Members, ESC Committee for Practice
Guidelines: ACC/AHA/ESC 2006 guidelines for the
management of patients with atrial fibrillation: a report
of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice
Guidelines (Writing Committee to revise the 2001 guide-
lines for the management of patients with atrial fibrilla-
tion) developed in collaboration with the European Heart
Rhythm Association and the Heart Rhythm Society.
Circulation, 114, e257-e354.
[4] Benjamin, E.J., Levy, D., Vaziri, S.M., D'Agostino, R.B.,
Belanger, A.J. and Wolf, P.A. (1994) Independent risk
factors for atrial fibrillation in a population-based cohort.
The Framingham Heart Study. Journal of the American
Medical association, 271, 1-11.
[5] Allessie, M.A., Boyden, P.A., Camm, A.J., Kléber, A.G.,
Lab, M.J., Legato, M.J., Rosen, M.R., Schwartz, P.J.,
Spooner, P.M., Van Wagoner, D.R. and Waldo, A.L.
(2001) Pathophysiology and prevention of atrial fibrilla-
tion. Circulation, 103, 769-777.
[6] Poirier, P., Bogaty, P., Garneau, C., Marois, L. and Du-
mesnil, J.G. (2001) Diastolic dysfunction in normoten-
sive men with well-controlled type 2 diabetes: impor-
tance of maneuvers in echocardiographic screening for
preclinical diabetic cardiomyopathy. Diabetes Care, 24,
5-10.
[7] Poirier, P., Bogaty, P., Philippon, F., Garneau, C., Fortin,
C. and Dumesnil, J.G. (2003) Preclinical diabetic car-
diomyopathy: relation of left ventricular diastolic dys-
function to cardiac autonomic neuropathy in men with
uncomplicated well-controlled type 2 diabetes. Metabo-
lism, 52, 1056-1061.
[8] Magyar, J., Rusznak, Z., Szentesi, P., Szucs, G. and
Kovacs, L. (1992) Action potentials and potassium cur-
rents in rat ventricular muscle during experimental dia-
betes. Journal of Molecular and Cellular Cardiology, 24,
841-853.
[9] Nishiyama, A., Ishii, D.N., Backx,.P.H., Pulford, B.E.,
Birks, B.R. and Tamkun, M.M. (2001) Altered K+ chan-
nel gene expression in diabetic rat ventricle: isoform
switching between Kv4.2 and Kv1.4. American Journal
of Physiology, 281, H1800-H1807.
[10] Gallego, M., Casis, E. and Izquierdo, M.J. (2000) Resto-
ration of cardiac transient outward potassium current by
norepinephrine in diabetic rats. Pflügers Archives, 441,
102-107.
[11] Xu, Z., Patel, K., Lou, M.F. and Rozanski, G.J. (2002)
Up-regulation of K+ channels in diabetic rat ventricular
myocytes by insulin and glutathione. Cardiovascular
Research, 53, 80-88.
[12] Pacher, P., Ungvari, Z., Nanasi, P.P. and Kecskeméti, V.
(1999) Electrophysiological changes in rat ventricular
and atrial myocardium at different stages of experimental
diabetes. Acta Physiologica Scandinavica, 166, 7-13.
[13] Yang, Q., Kiyoshige, K., Fujimoto, T., Katayama, M.,
Fujino, K., Saito, K., Nakaya, Y. and Mori, H. (1990)
Signal-averaging electrocardiogram in patients with dia-
betes mellitus. Japanese Heart Journal, 31, 25-33.
[14] Celiker, A., Akinci, A. and Özin, B. (1994) The sig-
nal-averaged electrocardiogram in diabetic children. In-
ternational Journal of Cardiology, 44, 271-274.
[15] Inoguchi, T., Ueda, F., Umeda, F., Yamashita, T. and
Nawata, H. (1995) Inhibition of intercellular communi-
cation via gap junction in cultured aortic endothelial cells
by elevated glucose and phorbol ester. Biochemical and
Biophysical Research Communications, 208, 492-497.
[16] Kuroki, T., Inoguchi, T., Umeda, F., Ueda, F. and
Nawata, H. (1998) High glucose induces alteration of
gap junction permeability and phosphorylation of con-
nexin-43 in cultured aortic smooth muscle cells. Diabetes,
47, 931-936.
[17] Inoguchi, T., Yu, H.Y., Imamura, M., Kakimoto, M.,
Kuroki, T., Maruyama, T. and Nawata, H. (2001) Altered
gap junction activity in cardiovascular tissues of diabetes.
Medical Electron Microscopy, 34, 86-91.
[18] Oku, H., Kodama, T., Sakagami, K., Puro, D.G. (2001)
Diabetes-induced disruption of gap junction pathways
within the retinal microvasculature. Investigative Oph-
thalmology and Visual Science, 42, 1915-1920.
[19] Poladia, D.P., Schanbacher, B., Wallace, L.J. and Bauer,
J.A. (2005) Innervation and connexin isoform expression
during diabetes-related bladder dysfunction: early struc-
tural vs. neuronal remodeling. Acta Diabetologica, 42,
147-152.
[20] Stilli, D, Lagrasta, C., Berni, R., Bocchi, L., Savi, M.,
Delucchi, F., Graiani, G., Monica, M., Maestri, R., Ba-
ruffi, S., Rossi, S., Macchi, E., Musso, E. and Quaini, F.
(2007) Preservation of ventricular performance at early
stages of diabetic cardiomyopathy involves changes in
myocyte size, number and intercellular coupling. Basic
Research in Cardiology, 102, 488-499.
[21] Task Force of the European Society of Cardiology and
the North American Society of Pacing and Electrophysi-
ology: Heart rate variability (1996) Standards of meas-
urement, physiological interpretation, and clinical use.
European Heart Journal, 17, 354-381.
[22] Daleau, P., Boudriau, S., Michaud, M., Jolicoeur, C. and
Kingma, J.G. Jr. (2001) Preconditioning in the absence
or presence of sustained ischemia modulates myocardial
Cx43 protein levels and gap junction distribution. Cana-
dian Journal of Physiology and Pharmacology, 79, 371-
378.
[23] Sarrazin, J.-F., Comeau, G., Daleau, P., Kingma, J.,
Plante, I., Fournier, D. and Molin, F. (2007) Reduced in-
cidence of vagally-induced atrial fibrillation and expres-
sion levels of connexins by n-3 polyunsaturated fatty ac-
ids in dogs. Journal of the American College of Cardiol-
ogy, 50, 1505-1512.
[24] Lin, H., Ogawa, K., Imanaga, I. and Tribulova, N. (2006)
Alterations of connexin 43 in the diabetic rat heart. Ad-
vance in Cardiology, 42, 243-254.
[25] Okruhlicova, L., Tribulova, N., Misejkova, M., Kucka,
M., Stetka, R., Slezak, J. and Manoach, M. (2002) Gap

P. Daleau et al. / HEALTH 2 (2010) 271-277
Copyright © 2010 SciRes http://www.scirp.org/journal/HEALTH/Openly accessible at
278
junction remodeling is involved in the susceptibility of
diabetic rats to hypokalemia-induced ventricular fibrilla-
tion. Acta Histochemica, 104, 387-391.
[26] Sheu, J.-J., Chang, L.-T., Chiang, C.-H., Sun, C.-K.,
Chang, N.-K., Youssef, A.A., Wu, C.-J., Lee, F.-Y. and
Yip, H.-K. (2007) Impact of diabetes on cardiomyocyte
apoptosis and connexin43 gap junction integrity. Role of
pharmacological modulation. International Heart Jour-
nal, 48, 233-245.
[27] Brink, P.R., Valiunas, V., Wang, H.Z., Zhao, W., Davies,
K. and Christ, G.J. (2006) Experimental diabetes alters
connexin43 derived gap junction permeability in short-
term cultures of rat corporeal vascular smooth muscle
cells. Journal of Urology, 175, 381-386.
[28] Howarth, F., Nowotny, N., Zilahi, E., El Haj, M. and Lei,
M. (2007) Altered expression of gap junction connexin
proteins may partly underlie heart rhythm disturbances in
the streptozotocin-induced diabetic rat heart. Molecular
and Cellular Biochemistry, 305, 145-151.
[29] Wolfle, S.E., Schmidt, V.J., Hoepfl, B., Gebert, A., Al-
colea, S., Gros, D. and de Wit, C. (2007) Connexin45
cannot replace the function of connexin40 in conducting
endothelium-dependent dilations along arterioles. Circu-
lation Research, 101, 1292-1299.
[30] Östgren, C.J., Merlo, J., Råstam, L. and Lindblad, U.
(2004) Atrial fibrillation and its association with type 2
diabetes and hypertension in a Swedish community.
Diabetes, Obesity and Metabolism, 6, 367-374.
[31] Movahed, M.-R., Hashemzadeh, M. and Jamal, M.M.
(2005) Diabetes mellitus is a strong, independent risk for
atrial fibrillation and flutter in addition to other cardio-
vascular disease. International Journal of Cardiology,
105, 315-318.
[32] Dupont, E., Ko, Y.-S., Rothery, S., Coppen, S.R., Baghai,
M., Haw, M. and Severs, N.J. (2001) The gap-junctional
protein connexin 40 is elevated in patients susceptible to
postoperative atrial fibrillation. Circulation, 103, 842-
849.
[33] Polontchouk, L., Haefliger, J.-A., Ebelt, B., Schaefer, T.,
Stuhlmann, D., Mehlhorn, U. and Kuhn-Regnier, F.
(2001) Effects of chronic atrial fibrillation on gap junc-
tion distribution in human and rat atria. Journal of the
American College of Cardiology, 38, 883-891.
[34] Kostin, S., Klein, G., Szalay, Z., Hein, S., Bauer, E.P.
and Schaper, J. (2002) Structural correlate of an atrial
fibrillation in human patients. Cardiovascular Research,
54, 361-379.
[35] Wetzel, U., Boldt, A., Lauschke, J., Weigl, J., Schirde-
wahn, P., Dorszewski, A., Doll, N., Hindricks, G., Dhein,
S. and Kottkamp, H. (2005) Expression of connexins 40
and 43 in human left atrium in atrial fibrillation of dif-
ferent aetiologies. Heart, 91, 166-170.
[36] Beauchamp, P., Yamada, K.A., Baertschi, A.J., Green,
K., Kanter, E.M., Saffitz, J.E. and Kléber, A.G. (2006)
Relative contributions of connexins 40 and 43 to atrial
impulse propagation in synthetic strands of neonatal and
fetal murine cardiomyocytes. Circulation Research, 99,
1216-1224.
[37] Zhang, Y., Xiao, J., Lin, H., Luo, X., Wang, H., Bai, Y.,
Wang, J., Zhang, H., Yang, B. and Wang, Z. (2007) Ionic
mechanisms underlying abnormal QT prolongation and
the associated arrhythmias in diabetic rabbits: a role of
rapid delayed rectifier K+ current. Cellular Physiology
and Biochemistry, 19, 225-238.
[38] Lengyel, C., Virag, L., Biro, T., Jost, N., Magyar, J.,
Biliczki, P., Kocsis, E., Skoumal, R., Nanasi, P.P., Toth,
M., Kecskemeti, V., Papp, J.G. and Varro, A. (2007)
Diabetes mellitus attenuates the repolarization reserve in
mammalian heart. Cardiovascular Research, 73, 512-
520.
[39] Casis, O., Gallego, M., Iriarte, M. and Sanchez-Chapula,
J.A. (2000) Effects of diabetic cardiomyopathy on re-
gional electrophysiologic characteristics of rat ventricle.
Diabetologia, 43, 101-109.
[40] Fernandez-Cobo, M., Gingalewski, C., Drujan, D. and
De Maio, A. (1999) Downregulation of connexin 43 gene
expression in rat heart during inflammation. The role of
tumour necrosis factor. Cytokine, 11, 216-224.
[41] Fukuda, T., Ikejima, K., Hirose, M., Takei, Y., Watanabe,
S. and Sato, N. (2000) Taurine preserves gap junctional
intercellular communication in rat hepatocytes under
oxidative stress. Journal of Gastroenterology, 35, 361-
368.