Vol.3, No.4, 295-300 (2011) Natural Science
http://dx.doi.org/10.4236/ns.2011.34038
Possible mechanism of increasing resistance of the
myocardium during combination of post infarction
remodeling and diabetes mellitus
Margarita V. Egorova*, Sergey A. Afanasiev, Dina S. Kondratyeva, Boris N. Kozlov, Sergey V. Popov
Laboratory of Molecular Cell Pathology and Genetic Diagnosis, Research Institute of Cardiology, Siberian Branch of Russian Academy
of Medical Science, Tomsk, Russia; *Corresponding Author:
Received 2 February 2011; revised 21 February 2011; accepted 13 March 2011.
ABSTRACT
It was shown that the energy metabolism of the
heart mitochondria of experimental animals and
patients is more resistant to damage at com-
bined postinfarction cardiosclerosis and dia-
betes in comparison with the individual pathol-
ogy. We found that the changes of free fatty acid
content and conjugation of the processes of
oxidation and phosphorylation in heart mito-
chondria are components of the metabolic sta-
bility of myocardium at the combined develop-
ment of postinfarction cardiosclerosis and dia-
betes mellitus. Our data demonstrate a direct
link between the violations of the processes of
oxidative phosphorylation and accumulation of
free fatty acids owing to change in activity of
endogenous phospholipases, in particularly, mi-
tochondrial phospholipase A2. Similar results
were obtained for intraoperative biopsy speci-
mens of patients’ hearts, and of adult Wistar
rats’ hearts. We hypothesized that the preserva-
tion of energy metabolism is a manifestation of
summing up of compensatory processes at de-
velopment of nonspecific response of cells to
damage at the early stages of pathological pro-
cess.
Keywords: Postinfarction Remodeling; Diabetes;
Heart Mitochondria; Fatty Acids; Phospholipase A2
1. INTRODUCTION
It is well known that many pathologies of the cardio-
vascular system are accompanied by increased activity
of endogenous phospholipases and, as a consequence, by
accumulation of free fatty acids [1] which, in turn, pro-
vokes uncoupling of the processes of oxidation and
phosphorylation in mitochondria [2]. A decrease of insu-
lin action on adipose tissue at diabetes mellitus (DM)
leads to the increased content of fatty acids in blood and
their intake into the myocardial cells. Myocardial con-
sequences of DM even in conditions of adequate oxygen
supply of myocardium resemble metabolic imbalance in
myocardium of patients with severe coronary heart dis-
ease (CHD) [3,4]. At DM, as at CHD, the corresponding
complex of pathophysiological changes appears either
because of the inability of mitochondria to oxidize the
entire volume of incoming fatty acids, or because of
critical lowering of coronary blood flow (at CHD), or
because of the enhanced transport of fatty acids in the
cytosol (at DM) [3,4]. It is logical to suppose that
hemodynamic changes on the DM background can in-
crease the probability of lethal outcome that is confirmed
by clinical studies [4,5].
However, there is data of manifestation of myocar-
dium resistance to ischemia (in vivo and in vitro) of
animals with short term of induced diabetes [6-8]: the
induction of diabetes on the background of postinfarc-
tion cardiosclerosis preserves, paradoxically, myocar-
dium contractile properties. Animals with combined pa-
thology are characterized by less pronounced changes in
glucose levels, body weight and heart [9,10].
The purpose of this study was evaluation of influence
of diabetes mellitus and postinfarction remodeling on
ability to oxidative phosphorylation of isolated heart mi-
tochondria of animals and humans both in the case of in-
dividual pathologies and in the case of their combination.
2. EXPERIMENTAL PART
2.1. Materials
The work was accomplished on mature male rats of
Wistar and intraoperative biopsy samples of patients.
2.1.1. Animals
5 groups for 8 rats were formed from animals:

M. V. Egorova et al. / Natural Science 3 (2011) 295-300 296
Group I - control animals,
Groups II and V – animals with induced DM,
Group III - rats after coronary occlusion,
Group IV - rats with combined pathology: DM was
induced after coronary occlusion after 2 weeks.
2.1.2. Patients
Studies were carried out on intraoperative atrial biop-
sies of male patients aged 52 - 69 years with underlying
diagnosis of coronary heart disease (CHD). The biopsy
specimens were divided into two groups:
The first group – CHD: patients with a diagnosis of
coronary heart disease (12 samples).
Underlying disease: CHD, exertional angina, func-
tional class III (FC). Multivascular atherosclerosis of
coronary arteries. Postinfarction cardiosclerosis (4 - 6
years after acute myocardial infarction). Chronic heart
failure (HF) by classifying the New York Heart Associa-
tion (NYHA) II, with preserved LV systolic function:
left ventricular ejection fraction (LVEF) > 45% (59% -
65%). Background pathology: arterial hypertension, de-
gree III, Risk 4, dislipidemia.
The second group – CHD + DII: patients with a diag-
nosis of CHD with a combination of diabetes mellitus
type 2 (6 samples).
Underlying disease: CHD, exertional angina FC III.
Postinfarction cardiosclerosis (after acute myocardial in-
farction – 4 - 6 years old). HF NYHA II, LVEF > 45%
(59% - 65%). Background pathology: arterial hyperten-
sion III, Risk, 4, dislipidemia. Concomitant disease: Dia-
betes mellitus type 2, moderate, subcompensated (Hb A1C
7.5%; fasting glucose 10 - 13 mmol/L, in urine – 40 - 45
g/day; cholesterol total 5.2 - 6.5 mmol/l, low density
lipoprotein (LDL) cholesterol > 3.0 mmol/l, high density
lipoprotein HDL < 0.9 mmol/l). Body mass index (BMI)
of 35 - 39 kg/m2, abdominal obesity 2.
The duration of the underlying disease from the time
of registration of 8 - 10 years, concominant disease—at
least 5 years.
Standard treatment: antianginal and antihypertensive
medicines, hypolipidemic agents (statin or/and fibrate),
and, for diabetes - hypoglycemic agent (metformin 1500 -
2000 mg/d).
Myocardial tissue samples of patients were frozen in
liquid nitrogen, prior to withstanding them at least 1
hour in cold Krebs-Henseleit buffer containing 20% di-
methyl sulfoxide (DMSO) [2]. Before the experiment,
biopsies thawed in warm Krebs-Henseleit buffer and
then used as freshly isolated tissue [2].
2.2. Methods
2.2.1. Simulation of Diabetes Mellitus
The development of diabetes was induced by a single
injection of streptozotocin (Sigma, USA) in a dose of 60
mg/kg, intraperitoneally, diluted ex tempera in 0,01
mol/L citrate buffer (pH 4.5) [6]. Diabetes mellitus was
verified by an increase of glucose concentration in rat
blood by 4,5 times and decrease of body weight of 56%
(p < 0.05) in comparison with the animals injected with
citrate buffer. Glucose concentration in blood serum was
determined with help of enzymatic – colorimetric test
(“Biocon Diagnostic”, Germany). The animals in Groups
II and IV were included into the study in 4 weeks after
the induction of diabetes mellitus, the animals in Group
V – in 6 weeks after.
2.2.2. Modeling of Postinfarction
Cardiosclerosis
Modeling of postinfarction cardiosclerosis in animals
was performed under deep ether anesthesia. The thoracic
cage of animals was opened and dissected into the two
ribs. After pericardiotomy, the coronary occlusion was
performed by ligation in the upper third of the left de-
scending coronary artery. Then, after removing air from
the thoracic cage cavity, the wound was sutured in layers.
After 40 days myocardial infarction was formed in these
animals: a morphological control of changes in the
structure of myocardial tissue was performed by means
of histological study, as previously described [1]. The
animals in this group had myocardial hypertrophy (Fig-
ure 1) (the heart size of the operated animals exceeded
the heart size of control rats, an average of 80%), and the
necrosis zone was about 12% of the total mass of the
hypertrophied left ventricle (Table 1). For the experi-
ment we used animals in 6 weeks after coronary occlu-
sion. Mitochondria obtained from control animal hearts
(sham-operated animals) were used as a control.
2.2.3. Measurementes
Heart mitochondria of patients and animals were re-
Figure 1. The typical form of rat heart. Note: A – the heart of
the control animal, B - the heart of the animal after 40 days
after coronary occlusion; 1 - place ligation, 2 - zone scar.

M. V. Egorova et al. / Natural Science 3 (2011) 295-300 297
Table 1. Weights of rats after experimental coronary occlusion.
Parameter sham-operated
animals
40 days after
coronary occlusion
Body weight (g) 287 ± 23.07 236.6 ± 3.07
Heart weight (mg) 955.9 ± 44.68 1491.2 ± 20.96 *
LV weight (mg) 620.5 ± 35.37 962.2 ±13.09*
Weight of the
damaged area (mg) 0 109.1 ± 1.44*
ceived using standard method of differential centrifuga-
tion in sucrose medium containing (mM) 300 of sucrose,
10 EDTA, 8 Tris, pH 7.4 [8]. For storage of mitochon-
dria, we used 250 mM sucrose solution.
The rate of oxygen uptake by mitochondria was de-
termined polarographically by Clark electrode. Meas-
urements were carried out in medium (pH 7.4) contain-
ing (mM): sucrose (300), KCl (10), KH2PO4 (5), succi-
nate (5), EGTA (1), MgCl2 (1,2), Tris (5). We used the
following additives: ADP - 100 uM, p-bromophenacyl
bromide (BPB) - 15 uM, arachidonic acid (AA) - 45 μM.
We used Sigma and ICN reagents.
The respiratory control (RC) was defined as the ratio
of the respiration rate at the maximum ATP synthesis to
respiration rate in the absence of ATP synthesis [9].
The rate of oxygen consumption is given in nM O2 per
minute per 1 mg of protein. The protein concentration in
the sample was determined by the standard Lowry me-
thod.
The content of fatty acids was determined in serum,
homogenates and mitochondrial suspension by enzy-
matic endpoint method (“DiaSys Diagnostic Systems”,
Germany) and calculated on 1 mg of protein.
2.3. Statistical Methods
All data are presented as a mean ± standard error of
the mean. The critical level of significance when testing
statistical hypotheses (p) was taken 0.05. In connection
with the fact that the distribution law of the studied pa-
rameters does not correspond to normal (Shapiro-Wilk
test, p> 0.05) law, we used nonparametric criteria to re-
veal differences in the groups. For independent data (one
index in various groups) used rank Mann-Whitney test.
For dependent data (various parameters in one group)
used Wilcoxon test.
3. RESULTS AND DISCUSSION
3.1. Change of the Content of Fatty Acids in
Serum and Myocardium
It is known that fatty acids are involved in the main-
tenance of membrane gomeostasis. Reorganization of
membrane lipid composition was modulated by “remod-
eling” of membrane phospholipids with phospholipase
A2 and arachidonic acid—this is a quick and subtle
regulation of membrane lipid composition in response to
changing concentrations and ratios of fatty acids [11].
The change in FFA concentration leads to a change in
the permeability of cardiomyocyte membrane, that, in
turn, influences functional activity of cardiomyocytes
[12,13]. We carried out research of fatty acid content in
serum, homogenates of the myocardium and in the mi-
tochondria suspension of animals and humans in all
groups studied (Table 2). It was found that fatty acid
content in blood serum of experimental animals was
reliably higher in all experimental groups in relation to
control, but in comparison between the experimental
groups no reliable differences were observed (Table 2).
There was no significant difference between control and
experimental animals in the homogenate. The most in-
teresting result was found at comparison of the data of
fatty acids content in mitochondrial suspension: a reli-
able difference in fatty acids content was observed not
only in relation of experimental animals to control ones,
but also between the groups (Table 2). The comparison
of data showed that the smallest difference in fatty acid
content in the mitochondrial suspension in relation to
control was observed at combination of pathologies.
Similarly, patients with CHD and CHD + DII did not
reveal statistically significant differences in fatty acid
content in the blood serum and myocardium homogenate,
but in a mitochondrial suspension with combination of
pathologies much less fatty acid content was observed
(Table 2).
3.2. Mitochondrial Respiration in Studied
Groups
Comparing the initial rate of mitochondrial respiration
in the studied groups of animals we found that in all ex-
perimental groups, this figure was significantly higher
than in the group of control animals (Table 3). In Group
II it increased by 4 times, in Group III –more than by 3
times, in Group IV with the combined pathology—only
by 2 times. Reducing the RC value in II-IV groups
demonstrated decrease in the conjugation degree of oxi-
dation and phosphorylation at these pathologies, how-
ever, in Group IV the uncoupling degree is also less
pronounced in comparison with individual pathologies
(Table 3).
The initial rate of oxygen uptake by human heart mi-
tochondria at CHD is almost by 2 times higher than at
combination CHD + DII (Table 3). Low RC indicates
uncoupling of oxidation and phosphorylation in both
groups, but lower rate of oxygen consumption (along
with higher RC) shows that this uncoupling is less pro-

M. V. Egorova et al. / Natural Science 3 (2011) 295-300 298
Table 2. The content of fatty acids in serum and myocardium of animals and humans.
The content of fatty acids (nM per mg protein)
Experimental groups
serum homogenate mitochondria
animals
Group I 0.38 ± 0.08 1.02 ± 0.14 0.83 ± 0.12
Group II 1.68 ± 0.21* 1.51 ± 0.17 5.83 ± 1.31*#^
Group III 0.83 ± 0.14* 1.19 ± 0.14 2.86 ± 1.15*#^
Group IV 1.45 ± 0.35* 1.35 ± 0.15 1.88 ± 0.78*#
patients
CHD 7.35 ± 0.93 9.33±1.62 7.2 ± 1.44#
CHD+DII 9.63 ± 0.81 8.15 ± 1.34 4.2 ± 1.36^#
Note. The experimental conditions and groups are described in the “Experimental part”. * - differences of the results in the column are statis-
tically significant as compared with Group I; # - differences of the results in each group are statistically significant as compared with each
other; ^ - differences between groups are statistically significant.
Table 3. Rate of oxygen consumption and respiratory control of heart mitochondria of animals and humans.
The rate of oxygen consumption, nM O2 per minute per mg of protein.
Experimental groups
initially +BPB
RC
animals
Group I 10.5 ± 1.8 10.6 ± 1.4 3.4 ± 0.09
Group II 44.7 ± 2.8* 38.0 ± 1.7*#^ 2.0 ± 0.01
Group III 35.2 ± 3.5* 21.1 ± 2.4*#^ 1.9 ± 0.02
Group IV 20.9 ± 1.5* 11.6 ± 1.5#^ 2.3 ± 0.05
patients
CHD 33.2 ± 1.5 18.7 ± 2.4#^ 2.0 ± 0.01
CHD+DII 17.6 ± 2.1 7.5 ± 1.2#^ 2.4 ± 0.03
Note. The experimental conditions and groups are described in the “Experimental part”. * - differences of the results in the column are statis-
tically significant as compared with Group I; # - differences of the results in each group are statistically significant when comparing between
indexes “initially” and “+ BPB”; ^ - differences between groups are statistically significant.
nounced in the case of a CHD and DII combination (Ta-
ble 3). Presented data and our earlier observations [10]
allow us to assert that at combination of pathologies car-
diomyocytes are accompanied by less pronounced viola-
tion of the energy metabolism both in animals and in
humans.
We have previously suggested and confirmed the as-
sumption that the violation of energy metabolism in rat
cardiomyocytes may be related to changes in the accu-
mulation of fatty acids and in the activity of endogenous
phospholipases [14]. Inhibition of phospholipase A2 by
p-bromophenacyl bromide (BPB) in postinfarction rat
cardiomyocytes resulted in normalization of cellular
respiration to the level of normal cardiomyocytes. Acti-
vation of phospholipase A2 by arachidonic acid or melit-
tin in cardiomyocytes of control rats significantly in-
creased the need of cells in oxygen [14].
In this study, in the presence of BPB, we observed a
pronounced decrease of the oxygen uptake rate by ani-
mals cardiomyocytes mitochondria of the III-IV Groups,
while in Group IV this figure was equal to that in control
group (Group I) (Table 3). Continuation of this trend is
observed for the human heart mitochondria: in the pres-
ence of BPB a oxygen uptake rate in patients with CHD
and CHD+DII decreased by 44% and 56% respectively
relative to the initial oxygen consumption rate (Table 3).
A significant reduction in the oxygen consumption
rate by mitochondria of animals and humans with a
combination of pathologies in the presence of BPB
demonstrates lability of mitochondrial phospholipase A2.

M. V. Egorova et al. / Natural Science 3 (2011) 295-300 299
It is the evidence of the greater stability of mitochondrial
membrane to damages and, consequently, gives hope
that violation of energy metabolism (closely associated
with membrane processes) is not irreversible.
3.3. Mitochondrial Respiration in Groups
with Different Terms of Diabetes
A comparative analysis of oxygen consumption rate
by rat heart mitochondria at different stages of strepto-
zotocin-induced diabetes showed that in animals of the
Group V a sharp difference of indices is observed not
only in comparison with control animals (Group I), but
also in comparison with diabetes at an earlier stage
(Group II) (Figure 2). Initial oxygen consumption rate
in Group V differs from one of control animals more
than by 10 times and more than 3 times greater than this
figure in comparison with Group II. The degree of un-
coupling of oxidation and phosphorylation becomes dan-
gerously high (RC - 1,5), indicating a critical violation
of energy in cardiomyocytes. Inhibition phospholipase
A2 by BPB does not lead to normalization of respiration
(Figure 2). When studying the influence of arachidonic
acid we observed significant stimulation of oxygen con-
sumption rate of heart mitochondria in Group I and, al-
beit to a much lesser extent, in Group II (Figure 2). We
are prone to consider effect as modulation of phospholi-
pase A2 activity [2]. Lack of stimulating effect of ara-
chidonic acid on oxygen consumption rate in the Group
V (Figure 2), in such a manner, confirms violation of
Figure 2. Effect of BPB and arachidonic acid (AA) on the rate
of oxygen consumption by mitochondria hearts of rats at dif-
ferent stages of diabetes. Note: The experimental conditions
and groups are described in the “Experimental part”. * - dif-
ferences of the results in the column are statistically significant
as compared with Group I; # - differences of the results in each
group are statistically significant when comparing between
indexes “initially” and “+BPB”; ^ - differences between groups
are statistically significant.
membrane remodeling and irreversibility of their dam
age. In these circumstances, even slight changes in myo-
cardial perfusion inevitably lead to cell death.
Our results and some literature data [6-10], at first
glance, are inconsistent with clinical observations about
rapidly growing degree of lethal outcome in such com-
bination of pathologies [10,5]. However, it is well
known that any disturbing factors action start the process
of nonspecific reaction in cells, developing in certain
consequence [15,16]. Early stages of pathological proc-
esses are connected with active start and use of compen-
satory processes to restore functional activity of a cell,
on the later stages this process becomes irreversible
[15,16]. It is possible that in our case cooperative effect
is observed: it is necessary to reveal what specific proc-
esses take part in it. Only the fact raises no doubt that
these processes are connected with activation of mem-
brane enzymes and reorganization of membrane. It is
also possible that along with this, the oxidation proc-
esses are switching to alternatives variances, as it occurs,
for example, during hypoxia (rapid oxidation of succinic
acid) [17].
One of the most powerful natural endogenous mecha-
nisms of adaptation during prolonged ischemia is a
“preconditioning phenomenon”. A lot of data testifying
to multiple levels of organization of this mechanism (see,
for example, reviews [18,19]) has been obtained in last
decades. Although our experimental conditions do not
meet the requirements of manifestation of the precondi-
tioning phenomenon (alternation of short episodes of
sublethal ischaemia and reperfusion), it is possible to
draw parallels. At preconditioning, in addition to short-
term adaptive reaction within 1-2 hours, developing de-
layed, less powerful but more prolonged (72 hours) reac-
tion, which was called “second window” [20]. Is it pos-
sible that combination of pathologies opens the “third
one”?
4. CONCLUSIONS
Thus, the results obtained testify to the fact that dis-
turbance of myocardial energy is the expression of non-
specific reaction of myocardial cells to injury both in
case of combined CHD + DII and in case of separate
pathologies. Our data demonstrate a direct link between
violations of the processes of oxidative phosphorylation
and accumulation of free fatty acids due to changes in
the activity of endogenous phospholipases, in particular,
mitochondrial phospholipase A2.
This article was prepared based on the research
funded by the Ministry of Education and Science under
the Federal Program “Research and development of prior
directions of scientific-technological complex of Russia
for 2007-2012” (HA No. 02.527.11.0007) and the grant

M. V. Egorova et al. / Natural Science 3 (2011) 295-300 300
of the 7th Framework Programme of Russia-EU (No.
241558).
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