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Abstract

Objectives: The mortality rate of chronic kidney disease (CKD) patients that have undergone renal replacement therapy is very high due to cardiovascular diseases (CVD). Some studies have indicated that cyclosporine A, a drug used to prevent transplant rejection, is associated with bone loss following transplantation. Furthermore, it has an oxidative effect on circulating lipids. Its prooxidant effect on cell membranes causes calcium release. This study aimed to examine whether or not renal transplantation result in improvement in oxidative stress and to assess the association between oxidized LDL (ox-LDL) and some variables in the prediction of CVD risk in Renal Transplantation (RT) patients that were compared with the control group. Material and methods: A total number of 30 CKD patients were recruited to evaluate time dependent changes in biomarker of OS before and after RT. The ox-LDL, lipid metabolism parameters, CsA, creatinine, calcium and phosphate were assessed both before RT, 10 days and 6 months after RT in comparison with the control group (n = 30). Results: Over 6 months, ox-LDL concentration changed from 79.7 ± 9.7 to 72 ± 7 mU/mL (p < 0.009). calcium phosphate level was positively correlated with the concentration of ox-LDL (R = 0.467, p = 0.011) and cyclosporine (R = 0.419, p = 0.024) 6 months after transplantation. Conclusion: The findings indicated that restoring renal function by transplantation, improves uremia induced oxidative stress. calcium phosphate product, as an independent risk factor for CVD, correlates with ox-LDL before RT and 6 months after RT. Calcium phosphate product correlates with cyclosporine in the RT group, too.
Original article | artigO Original
147
Authors
Adele Soltani 1
Hassan Argani 1
Hooman Rahimipour 1
Fateme Soleimani 1
Foroug Rahimi 1
Faranak Kazerouni 1
1 University of Medical
Science.
Submitted on: 05/13/2015.
Approved on: 01/25/2016.
Correspondence to:
Faranak Kazerouni.
University of Medical
Science.
Darband Street, Tajrish,
Tehran, Iran.
CEP: 1939504618
E-mail: med.lab.sc.dept@
gmail.com
Oxidized LDL: As a risk factor for cardiovascular disease in
renal transplantation
LDL oxidada: Como um fator de risco para doença cardiovascular
no transplante renal
Objetivos: A taxa de mortalidade de pa-
cientes com doença renal crônica (DRC),
que tenham sido submetidos à terapia de
substituição renal, é muito elevada devido a
doenças cardiovasculares (DCV). Alguns es-
tudos indicaram que a ciclosporina A (CsA),
um medicamento utilizado para prevenir
a rejeição de transplante, está associada à
perda óssea após o transplante. Além disso,
ela tem um efeito oxidante sobre os lipíde-
os circulantes. Seu efeito pró-oxidante nas
membranas celulares provoca a liberação de
cálcio. Este estudo teve como objetivo anali-
sar se o transplante renal pode ou não resul-
tar em melhora no estresse oxidativo (EO);
e avaliar a associação entre a LDL oxidada
(LDL-ox) e algumas variáveis na predição do
risco de DCV em pacientes transplantados
renais (TR), comparados com o grupo con-
trole. Materiais e Métodos: Um total de 30
pacientes com DRC foram recrutados para
avaliação das alterações dependentes do tem-
po no biomarcador de EO antes e após TR.
Foram avaliados: LDL-ox, parâmetros do
metabolismo dos lipídeos, a CsA, creatinina,
cálcio e fosfato tanto antes do TR, 10 dias
e 6 meses após o TR, em comparação com
o grupo controle (n = 30). Resultados: após
6 meses, a concentração de LDL-ox mudou
de 79,7 ± 9,7-72 ± 7 mU/ml (p < 0,009). O
nível de fosfato de cálcio foi positivamente
correlacionado com a concentração de LDL-
-ox (R = 0,467, p = 0,011) e ciclosporina (r
= 0,419, p = 0,024) 6 meses após o trans-
plante. Conclusão: Os resultados indicaram
que a restauração da função renal pelo trans-
plante, melhora o estresse oxidativo induzido
pela uremia. O produto de fosfato de cálcio,
como um fator de risco independente para
DCV, correlaciona-se com o LDL-ox antes
do TR e 6 meses após o TR. O produto de
fosfato de cálcio também se correlaciona
com a ciclosporina no grupo TR.
Resumo
Palavras-chave: doenças cardiovascula-
res; estresse oxidativo; fosfatos de cálcio;
transplante de rim.
Objectives: The mortality rate of chronic
kidney disease (CKD) patients that have
undergone renal replacement therapy is
very high due to cardiovascular diseases
(CVD). Some studies have indicated that
cyclosporine A, a drug used to prevent
transplant rejection, is associated with
bone loss following transplantation. Fur-
thermore, it has an oxidative effect on
circulating lipids. Its prooxidant effect on
cell membranes causes calcium release.
This study aimed to examine whether
or not renal transplantation result in
improvement in oxidative stress and to
assess the association between oxidized
LDL (ox-LDL) and some variables in the
prediction of CVD risk in Renal Trans-
plantation (RT) patients that were com-
pared with the control group. Material
and Methods: A total number of 30 CKD
patients were recruited to evaluate time
dependent changes in biomarker of OS
before and after RT. The ox-LDL, lipid
metabolism parameters, CsA, creatinine,
calcium and phosphate were assessed
both before RT, 10 days and 6 months
after RT in comparison with the control
group (n = 30). Results: Over 6 months,
ox-LDL concentration changed from
79.7 ± 9.7 to 72 ± 7 mU/mL (p < 0.009).
calcium phosphate level was positively
correlated with the concentration of ox-
LDL (R = 0.467, p = 0.011) and cyclo-
sporine (R = 0.419, p = 0.024) 6 months
after transplantation. Conclusion: The
findings indicated that restoring renal
function by transplantation, improves
uremia induced oxidative stress. calcium
phosphate product, as an independent
risk factor for CVD, correlates with ox-
LDL before RT and 6 months after RT.
Calcium phosphate product correlates
with cyclosporine in the RT group, too.
AbstRAct
Keywords: calcium phosphates; cardio-
vascular diseases; kidney transplantation;
oxidative stress.
DOI: 10.5935/0101-280 0.20160023
J Bras Nefrol 2016;38(2):147-152
Oxidized LDL and renal transplantation
148
IntRo duct Ion
Cardiovascular disease (CVD) is the major cause of
death in patients with chronic kidney disease (CKD)
that undergo renal replacement therapy (RRT). The
predicted risk is 3.5-50 times more than normal
population that causes about 40% of total deaths
among patients who receive RRT.1-5 Patients with end
stage renal disease (ESRD) have a high prevalence of
oxidative stress (OS) as a risk factor for cardiovascular
events.3,6-8
Atherosclerosis progression occurs after starting
hemodialysis; therefore, dialysis therapy or uremic factors
may be a cause of OS in these patients.9 Dyslipidemia,
such as high levels of low-density lipoprotein (LDL),
is another risk factor that accelerates atherogenesis
process. Chronic administration of immunosuppressive
drugs such as cyclosporine A (CsA) result in altering
plasma lipoprotein metabolism. For this reason,
atherogenesis is a common problem that is observed
after kidney transplantation.10-13 Reports have shown
that CsA has prooxidant effect on cell membranes and
promotes oxidation of circulating lipids.14,15 LDL is easily
susceptible to oxidation in OS conditions that results in
oxidized LDL (ox-LDL) form, and has some atherogenic
features.16,17
This study was conducted to determine if there
is further improvement in oxidative stress status of
kidney transplant recipients with regard to serum
ox-LDL levels before and after transplantation.
According to Regmi et al.,18 there was a significant
association between higher value of Ca2+ × PO4, micro
inammation, and oxidative stress in CKD patients.
Threfore, it can be concluded that the medication
in transplanted patients is related to oxidative stress
and created inflammatory process in CKD patients
gradually. The other aim of this study was to assess
ox-LDL correlation with serum Ca2+ × PO4.
mAteRIAls And metho ds
SubjectS
For this study, thirty eligible patients for kidney
transplantation from Shahid Modarres hospital in
Tehran were recruited. A control group consisting of
30 healthy participants was used for comparison. The
participants of the control group were normolipidemic
and did not have any disease.
One day before renal transplantation, induction
therapy with CsA was started for all patients according
to the protocol of transplant unit. The exclusion
criteria that were considered were as follows:
Patients who were on HD less than 6 months
1. History of active infection within recent 3
months
2. History of malignancy
3. History of chronic liver disease
4. Acute rejection after transplantation.
Inclusion criteria in the RT group were patients
treated with conventional triple immunosuppressive
drugs composed of cyclosporine, mycophenolic
acid and Prednisolone with no evidence of acute
allograft rejection during the last 3 months before
taking part in this study. The causes of renal failure
in these patients were diabetic nephropathy, chronic
glomerulonephritis, polycystic kidney disease,
hypertensive ischemic nephropathy, obstructive
nephropathy and unknown etiology. We had no
post-transplant diabetes melitus in the RT patients.
All of diabetes melitus patients in the RT group
were diabetic before RT (during hemodialysis). The
patients, before RT, were under regular hemodialysis
for at least 6 months 3×4 h/week by synthetic high-
flux membranes with Fresenius-2008B hemodialyser.
All participants signed a consent form, which was
approved by the Ethical Committee Board of Shahid
Beheshti University (IRB approval number is 61825).
Age, sex, body mass index (BMI = weight (kg)/
height (m)*2 and smoking habits of both groups were
recorded.
metho ds
Three blood samples were obtained after 12-hours
of fasting from patients: before transplantation, on
the discharge day (10 days after transplantation)
and 6 months after transplantation. Samples were
centrifuged at 3,000×g for 10 minutes at room
temperature within 1 hour after collection and stored
at − 80°C until the assays were performed.
Serum total cholesterol, high-density lipoprotein
(HDL) cholesterol, triglycerides, creatinine and urea
were measured by a Hitachi 917 analyzer using
Roche reagents (Roche, Mannheim, Germany). Low
density lipoprotein (LDL) cholesterol was calculated
according to the Friedewald formula. Very low
density lipoprotein (VLDL) cholesterol was computed
by dividing triglyceride by 5. Serum total calcium and
serum phosphate were measured by using commercial
kits (Pars Azmoon Co).
J Bras Nefrol 2016;38(2):147-152
Oxidized LDL and renal transplantation
149
Ox-LDL concentration was measured by a
competitive enzyme-linked immuno absorbent assay
method, via using a novel commercially available
ELISA kit (Cusabio biotech Co, LTD, Wuhan,
China), with detection range between 1.56 mU/mL
and 100 mU/mL. The intra-assay and inter-assay
variations were < 8% and < 10%, respectively. The
standard curve concentrations used for the ELISAs
were 100 mU/mL, 50 mU/mL, 25 mU/mL, 12.5 ng/
mL, 6.25 mU /mL, 3.12 mU/mL, 1.56 mU/ml and 0
mU/ml. The minimum detectable dose of human ox-
LDL is < 0.78 mU/mL.
CsA concentration was measured by using RIA
kit in whole blood, only in renal transplant recipients
(DIA source Immuno Assays S.A. - Rue du Bosquet,
2 - B-1348 Louvain-la-Neuve - Belgium). Intra-assay
and inter-assay variation were found below or equal
to 9.2 % and 7.3 %. The measurement range of Cs A
(from analytical sensitivity to highest calibrator) was
1.61 to approximately 2500 ng/mL.
StatiStical analySiS
Results were presented as numbers, percentages, and
mean with standard deviation (mean ± SD) when
appropriate.
Based on data distribution, repeated measures
ANOVA were applied to compare variables of
groups, followed by Tukey post-hoc to analyze
the data. Pearson’s correlation test was performed
to examine the correlation between all variables.
Multiple regression analysis was used to investigate
the relationships between the concentration of ox-
LDL and lipid, lipoprotein, Ca2+ × PO4 and CsA. p
values 0.05 were considered statistically significant.
Analyses were adjusted for age, gender, current
cigarette smoking, regular physical activity and BMI,
and were carried out using GraphPad Prism software
(Version 5).
Results
Thirty healthy adults (17 males; 13 females) and 30
patients (16 males; 14 females) took part in the study.
The mean age of patients was 42 ± 16 years. Results
are shown in Table 1, and Figures 1, 2, and 3.
Table 1 shows mean with standard deviation of
demographic data and laboratory findings of the
patients and the control group. The groups were
matched according to age, gender and BMI. As can
be seen, the total plasma ox-LDL concentration was
significantly higher among the patients before RT
as compared to the amount recorded 6months after
RT and the control group (79.7 ± 9.7 mu/ml versus
72 ± 7 mu/ml and 68.9 ± 4 mu/ml; p = 0.009, p =
0.001). In addition, the values of lipid metabolism are
summarized here.
Ox-LDL levels had no correlation with gender,
age, type of dialysis membrane, smoking status,
physical activity, appetite, dialysis duration before RT
and primary cause of CKD.There were no statistical
differences between ox-LDL levels before RT and
10 days after RT (p = 0.958), (Fig. 1). There was a
significant decrease in ox-LDL following RT, which
was marked significant after 6 months (p < 0.009).
As expected, urea and creatinine concentration
decreased after a successful RTT. As can be seen, Ca2+
× PO4 before transplantation is higher compared to
the control group and 10 days and 6 months after RT
(p < 0.0001). The Pearson correlation analysis showed
that Ca2+ × PO4 level was positively correlated with
the concentration of ox-LDL (R = 0.467, p = 0.011)
and cyclosporine (R = 0.419, p = 0.024) 6 months
after transplantation (Figs. 2,3). Also this correlation
analysis showed ox- LDL was correlated with Ca2+ ×
PO4 before RT (R = 0. 467, p = 0.011).
In the model of multiple stepwise regression
analysis, ox-LDL was selected as the dependent
variable, and lipid, lipoproteins, calcium, Ca2+ × PO4
and CsA were considered as independent variables.
This model demonstrated that ox-LDL concentration
in RT group was associated positively with Ca2+ ×
PO4 level (R2 = 0.219, β = 0.456, p = 0.013).
dIscu ssIo n
In this study, the researchers hypothesized that
transplantation would improve oxidative stress
marker, ox-LDL, that is also proposed as a risk factor
for the development of atherosclerosis and kidney
failure in renal transplantation.19-23 The researchers
also investigated its correlation with other variable
such as ca+2, p, Ca2+ × PO4 and lipid profile.
The result of this study showed that serum Ox-
LDL significantly decreased after RT and Serum Ox-
LDL correlated with Ca2+ × PO4 in serum before and
6 months after RT.
RT is the choice treatment for patients with ESRD
that results in better survival and quality of life rather
than dialysis (before RT). However, cardiovascular
(CV) events remain considerably high in these
J Bras Nefrol 2016;38(2):147-152
Oxidized LDL and renal transplantation
150
Figure 1. Comparison of ox-LDL level before transplant, 10 days after
transplant and 6 months after it with control group. *= significant
difference between before renal transplantation and controls, **=
significant difference after 6 months compare to control group.
Figure 2. Scatter plot showing the positive relationship between
oxidized LDL (ox-LDL) and Ca2+ × PO4 after 6 months.
patients even after RT. CV events in RT recipients
arise earlier and are along with rapid progression and
calcication; CKD patients and healthy population
experience these processes differently. For RT
recipients, modification in CV risk factors such as
oxidative stress may partially lead to better survival
after renal transplantation.3,7,19
The initial finding indicated that ox-LDL decreased
after RT in comparison with its serum level before
transplantation. After 6 months, these values were in
agreement with those of the control group. In line with
this result, Simmons et al.7 reported significant decline
in plasma Free F2 Isoprostane content, an oxidative
biomarker, after transplantation that persisted for 2
months. In addition, Kimak et al.11 reported that Ox-
LDL decreased in RT patients compared to HD group
after 6 and 12 months. However, this reduction was
not as much as the control group. Simmons et al.7
reported that ox-LDL level decreased even one week
after RT. However, in this study, its increase was
observed after 10 days. Its higher level compared
to the results of this study may be due to the kind
Parameters Pre-Tplt Post-Tplt after 10
days
Post-Tplt after 6
months Control
Number/sex 30 (16M, 14F) 30 (16M, 14F) 30 (16M, 14F) 30 (17M, 13F)
Age (year) 42.0 ± 16.0 42.0 ± 16.0 42.6 ± 16.0 40.0 ± 8.0
BMI (kg/m2) 25.5 ± 5.0 24.5 ± 3.0 25.0 ± 2.0 25.0 ± 3.0
Urea (mg/dl) 128.0 ± 40.0*** 56.0 ± 19.0* 55.0 ± 19.0* 35.0 ± 5.5
Creatinine (mg/dl) 7.7 ± 2.0*** 1.2 ± 0.1 1.2 ± 0.1 0.98 ± 0.1
Total Chol (mg/dl) 152.0 ± 32.0 186.0 ± 17.0 192.0 ± 20.0^177.0 ± 23.0
LDL- Chol (mg/dl) 78.0 ± 36.0*** 104.0 ± 17.0 110.0 ± 22.0^^ 105.0 ± 19.0
HDL-Chol (mg/dl) 43.0 ± 12.0 44.0 ± 7.0 44.0 ± 6.0 45.5 ± 3.0
Triglyceride (mg/dl) 157.0 ± 86.0*** 187.7 ± 36.0 189.0 ± 26.0^^^ 133.0 ± 27.0
VLDL- Chol (mg/dl) 31.4 ± 17.0 37.5 ± 7.0 38.0 ± 5.0*** 26.7 ± 9.0
Calcium (mg/dl) 9.1 ± 1.2* 9.4 ± 0.3 9.4 ± 0.3 9.6 ± 0.5
Phosphorus (mg/dl) 6.4 ± 1.7** 4.2 ± 0.8 4.1 ± 0.7 4.5 ± 0.7
CyclosporineA (ng/dl) N/A 263.0 ± 57.0 154.0 ± 47.0 N/A
Ox-LDL (mU/ml) 79.7 ± 9.7** 81.2 ± 8.0** 72.0 ± 7.0^^ 68.9 ± 4.0
Ca2+ ×PO4 (mg2/dL2) 58.3 ± 17.0*** 39.5 ± 8.1 38.8 ± 6.3 43.4 ± 7.4
*p < 0.05, **p < 0.01, ***p < 0.001 controls versus patients; ^ p < 0.05,^^ p < 0.01,^^^ p < 0.001 Pre-Tplt versus Post-Tplt. Data are shown as
mean ± SD; Tplt: transplantation; BMI: body mass index; M: male; F: female; Chol: cholesterol; LDL: low-density lipoprotein; HDL: high-density
lipoprotein; VLDL: very low density lipoprotein; Ox-LDL: oxidized LDL; N/A: not applicable.
tAble 1 Demographic Data anD laboratory parameterS for patientS anD controlS
J Bras Nefrol 2016;38(2):147-152
Oxidized LDL and renal transplantation
151
Figure 3. Scatter plot showing the positive correlation between
cyclosporine A and Ca2+ × PO4 after 6 months.
of immunosuppression drug. The patients in this
study consumed just Cs A and in Simmons et al. 7
study half of patients were treated with Tacrolimus.
Venkiteswaran et al.17 showed that LDL was isolated
from recipients’ plasma treated with Cs A showed
significantly higher susceptibility to oxidation as
compared to tacrolimus.
The results of this study also indicated
increased levels of cholesterol, LDL, VLDL and
triglyceride, while HDL concentration was normal.
Immunosuppressive drugs are necessary to prevent
allograft rejection. It seems that these medications
could exacerbate dyslipidemia or hyperlipidemia.24-26
The concentration of Ca2+ × PO4 6 months after
transplantation was lower than that of the control
group and before transplantation. Both calcium and
phosphate absorptions were impaired in patients with
CKD. Calcium absorption improved dramatically
after successful renal transplantation, while phosphate
absorption remained the same. The interaction of
various drugs with intestinal transport mechanisms
for phosphate could be an important factor in this
regard, and long-term steroid administration and
cyclophosphamide treatment reduced phosphate
absorption. Also, the increased secretion of gastric
acid produced by prednisolone may possibly have a
role in reducing phosphate absorption in transplant
recipients.27
The concentration of Ca2+ × PO4 was higher before
transplantation compared to the control group. The
elevation in serum phosphate leads to the increase of
Ca2+ × PO4. Thus, the increase in phosphorus, directly
and indirectly, leads to an increase in parathyroid
cells and increased synthesis and secretion of PTH.
Increased secretion of PTH increases blood level of
calcium ions, which increases the level of Ca2+ × PO4
product.28
Based on the results obtained in this study, there
is a positive correlation between ox-LDL and Ca2+ ×
PO4 (as the predictor of CVD risk in CKD patients)
and also between Ca2+ × PO4 and cyclosporine. The
multiple stepwise regression analysis demonstrated
that in RT group ox-LDL concentration was associated
positively with Ca2+ × PO4 level after 6 months. Regmi
et al.18 also found a significant association between
higher value of Ca2+ × PO4, micro inammation and
oxidative stress in CKD patients. They showed that
oxidative stress and inflammation markers such as
anti-oxLDL and hsCRP were associated with higher
serum Ca2+ × PO4 levels. So, it can be concluded that
the medication in transplanted patients is related to
oxidative stress, and created the inflammatory process
in patients gradually.
In conclusion, the findings indicate that restoration
of renal function by transplantation improves uremia
induced oxidative stress. Ca2+ × PO4 product, as an
independent risk factor for CVD, correlates with ox-
LDL (before RT and 6 months after RT) and serum
level of cyclosporine (in the RT group).
The present study has certain limitations such as the
small sample size and the absence of 25(OH) vitamin
D levels. The cross sectional design did not clearly
elucidate the cause-and-effect of results. However, it is
anticipated that this work can contribute to detecting
populations with cardiovascular risk factors.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
Ethical approval: All procedures performed in
studies involving human participants were in accordance
with the ethical standards of the institutional research
committee and with the 1964 Helsinki declaration and
its later amendments or comparable ethical standards.
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gfh891
... 24 Lack of glycemic control activates hepatic mechanisms that rise lipoprotein synthesis, increasing LDL levels, and reducing HDL levels. These factors are strongly associated with cardiovascular risk, 23,25 which supports the metabolic results of this study. Results similar to these were found in our previous study, revealing that a more meticulous analysis of biochemical components allows a better comprehension of the MS progression status in the elderly population. ...
... The LDL role associated with cardiovascular impairment may trigger CVD development, and this association may be enhanced by factors such as a smoking habit, DM, and hypertension. 23,25,31 DM was identified in this study as predictive of high cardiovascular risk and is one of the factors involved in the MS process. Some studies cite MS as a predictor for the DM diagnosis. ...
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... Vascular smooth muscle cell proliferation is one of the major contributors to atherosclerosis, thus its risk factors are being extensively studied. One of them is ox-LDL, a result of ox-LDL oxidation [18,19,20]. In addition, efforts to improve and prevent atherosclerosis are continuing. ...
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Background Currently, gene therapy for cardiovascular diseases has been widely concerned, but its mechanism is still unclear. Objective Recently miRNAs have been recognized as a key regulator in vascular smooth muscle cells (VSMCs) which involved in the formation of atherosclerosis. The aim of the study was to explore the role of miR-129-5p in regulation of HMGB1 involving a PI3K/Akt signal pathway as well as the proliferation and migration in A7r5 cells induced by ox-LDL. Methods Cell viability, proliferation and migration were conducted by CCK-8, colony formation, wound healing assay and transwell assay. The expressions of miR-129-5p and HMGB1 were detected by real-time quantitative-qPCR (RT-qPCR) and western blot. Luciferase assay was used to confirm that miR-129-5p directly targeted HMGB1. Results The expression of miR-129-5p in A7r5 cells induced by ox-LDL was significantly decreased in comparison with the control cells. Cell viability, proliferation and migration of A7r5 cells induced by ox-LDL were increased. MiR-129-5p could down-regulate the expression of HMGB1 in A7r5 cells. More studies showed that miR-129-5p could inhibit cell viability, proliferation on and migration of A7r5 cells induced by ox-LDL and target HMGB1 to regulate PI3K/Akt signal pathway. Conclusion miR-129-5p could inhibit PI3K/Akt signal pathway by target HMGB1 and further restrain the cell viability, proliferation and migration of A7r5 cells induced by ox-LDL.
... is associated with AS, and is formed as a result of ox-LDL oxidation (32)(33)(34). In addition, further research has focused on improving and preventing the development of AS. ...
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The mechanisms underlying gene therapy for the treatment of cardiovascular diseases remain to be elucidated. microRNAs (miRs) have been recognized as key regulators in vascular smooth muscle cells, which are involved in the formation of atherosclerosis. The present study aimed to explore the role of miR-129-5p in the regulation of high-mobility group box 1 protein (HMGB1) and the PI3k/Akt signaling pathway, and further explore the role of miR-129-5p in the viability and migration of A7r5 cells induced by oxidized low-density lipoprotein (ox-LDL). Cell viability, viability and migration were determined using Cell Counting Kit-8, colony formation, wound healing and Transwell assays. The expression levels of miR-129-5p and HMGB1 were detected using reverse transcription-quantitative PCR and western blotting. A dual-luciferase assay was used to confirm the association between miR-129-5p and HMGB1. RT-qPCR results in the present study demonstrated that the expression levels of miR-129-5p in A7r5 cells induced by ox-LDL were significantly decreased, compared with the control cells. Moreover, the viability and migration of A7r5 cells induced by ox-LDL were increased compared with control group. Western blot and RT-qPCR results showed that miR-129-5p decreased the expression of HMGB1 in A7r5 cells compared with control group. The present results demonstrated that miR-129-5p inhibited the viability, viability and migration of A7r5 cells induced by ox-LDL, and directly targeted HMGB1 to regulate the PI3k/Akt signaling pathway. In conclusion, miR-129-5p inhibited the PI3k/Akt signaling pathway by directly targeting HMGB1, and reduced the viability, viability and migration of A7r5 cells induced by ox-LDL.
... Quando associados ao histórico clínico do paciente, doenças de base como dislipidemia podem acelerar prejudicialmente estes eventos e ocasionar complicações a estes pacientes. Além disso, as lipoproteínas de baixa densidade e seu potencial risco para eventos adversos, como a aterosclerose, e menciona que estas lipoproteínas podem sofrer com o estresse oxidativo presente nestes pacientes devido aumento de toxinas no organismo e se tornarem lipoproteínas de baixa densidade oxidadas, com potencial fator aterogênico 19 . ...
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Severity of heart disease of almost all types, as well as mortality risk associated with heart disease, increases in step with severity of kidney disease, although not necessarily in a linear fashion. Heart failure is more common and just as lethal as ischemic heart disease in patients with severe chronic kidney disease (CKD). The incidence of nonfatal heart disease in dialysis and transplant populations has now been described in detail. Although standard risk factors for heart disease that are more common among patients with CKD than in the general population do not adequately explain the greatly increased risk of heart disease in patients with severe CKD, neither do as yet identified “nontraditional” risk factors. However, in addition to the factors not common in the general population, such as anemia, hyperphosphatemia, and markers of systemic inflammation, patients with CKD in the modern era may also exhibit excessive thrombotic tendencies. Screening for heart disease in this population relies mainly on dobutamine stress echocardiography or nuclear scintigraphy. The role of electron beam CT (EBCT) scanning is currently controversial. The indications for coronary angiography are the same for patients with CKD as for the general population, but patients with CKD are at greatly increased risk for contrast-associated nephropathy, the least controversial preventive therapy, which consists of isotonic saline and N-acetylcysteine. Finally, patients with CKD do not currently receive adequate medical therapy for prevention and treatment of heart disease.
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Cardiovascular diseases are accompanied by active oxygen species and organic free radical generation. The aim of this study was to examine the possibility of using oxidized low-density lipoprotein (oxLDL) as a new diagnostic biomarker. Epidemiological study in populations of Estonia (782 subjects) and Russia (1433 subjects) was carried out in 2007-2009. The screening procedure included standard epidemiological methods. Oxidative stress was assessed by measuring the level of oxLDL using immunoassay method. Positive correlation between the levels of oxLDL and LDL cholesterol was indicated in blood of patients from estonian (r = 0.61; P < 0.05) and russian (r = 0.56; P < 0.05) populations. In russian population oxLDL/HDL cholesterol ratio was higher in the groups with highest risk of atherosclerosis development or manifest coronary artery disease (CAD). Cholesterol-rich low density lipoproteins are also more oxidized. Estimation of oxLDL/HDL ratio may be used as an independent biochemical marker for atherosclerosis.
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Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox-LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL-C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman's rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=-0.306, P=0.012), LDL-C (R=-0.283, P=0.020), and non-HDL-C (R=-0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-β-HDL particles, and thus accelerate reverse cholesterol transport, which may be beneficial for Tx patients. Further studies are necessary to confirm this.
Article
Objective: The high incidence of cardiovascular diseases in chronic renal failure (CRF) and hemodialyzed (HD) patients is now well established and the involvement of oxidative stress has been hypothesized in these phenomena. The aim of our study was to evaluate the level of oxidative stress in healthy controls (CTL) compared with CRF and HD patients before (pre-HD) and after (post-HD) the dialysis session, carried out on a high biocompatible polyacrylonitrile membrane AN69. Methods: Several indicators of the extracellular redox status were evaluated in plasma. The ascorbyl free radical (AFR) was directly measured using electron spin resonance spectroscopy (ESR) and expressed with respect to the vitamin C level to obtain a direct index of oxidative stress. Indirect plasma parameters such as vitamin E, thiol and uric acid levels were also quantified. The plasma antioxidant status (PAS) was evaluated by the allophycocyanin test. Nitric oxide (NO) stable-end metabolites: nitrites and nitrates (NO(x)), were measured in plasma. Results: In CRF patients, vitamin C and thiol levels were low, and the AFR/vitamin C ratio high compared with the CTL. On the other hand, PAS and uric acid levels were shown to be higher in CRF patients. After the dialysis session, vitamin C level decreased and AFR/vitamin C ratio increased. The thiol levels were shown to be increased, in return PAS and uric acid levels were significantly lower after the dialysis session. NO(x) levels rose during CRF, but were significantly decreased after the dialysis procedure. No differences in vitamin E status were observed between CTL, CRF and HD patients. Conclusion: Our study demonstrates that profound disturbances in the extracellular redox system occur during the course of chronic renal failure and hemodialysis, and may provide an explanation for the cardiovascular complications in these patients.
Article
Patients on dialysis display increased inflammation (IF) and oxidative stress (OS). Diabetes mellitus (DM) may increase both processes. The role of transplantation in this situation is unknown. Herein we have assessed the evolution of IF and OS following grafting and its relationship to a prior diagnoses of DM and to kidney function at 1 year. This prospective study included 131 dialysis patients who underwent transplantation of mean age 54 +/- 12 years, including 68% men with 19.5% showing prior DM. The following markers of IF and OS were determined prior to and at 3 months after grafting: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), soluble TNFalpha receptor (sTNFalpha-R), soluble IL-2 receptor (sIL-2R), oxidized LDL (oxLDL), and anti-oxLDL antibodies (oxLDLab). The evolution (ratio) of these markers was assessed by dividing the values at 3 months by the prior ones. Modification of Diet in Renal Disease (MDRD) was determined at 12 months. Patients with prior DM were older (P = .034). There were no differences in the pregrafting phase between diabetics and nondiabetics in relation to IF or OS. IF and OS showed a worse evolution postgrafting among patients with prior DM. At 1 year postgrafting renal function was greater in patients without prior DM (P = .022). There was an inverse correlation between the ratios of markers and kidney function at 1 year postgrafting: TNFalpha: r = -.235 (P = .012); sIL-2R: r = .441 (P < .001); and sTNFalpha-R: r = .225 (P = .017). In the pregrafting phase, there were no differences between patients with or without DM in terms of IF and OS. These differences appeared in the postgrafting phase: patients with DM showed greater IF and OS, an increase that may explain the poor kidney function observed at 1 year among patients with DM.
Article
Chronic kidney disease (CKD) affects approximately 13% of the U.S. population and is associated with increased risk of cardiovascular complications. Once renal replacement therapy became available, it became apparent that the mode of death of patients with advanced CKD was more likely than not related to cardiovascular compromise. Further observation revealed that such compromise was related to myocardial disease (related to hypertension, stiff vessels, coronary heart disease, or uremic toxins). Early on, the excess of cardiovascular events was attributed to accelerated atherosclerosis, inadequate control of blood pressure, lipids, or inflammatory cytokines, or perhaps poor glycemia control. In more recent times, outcome research has given us further information that relates even lesser degrees of renal compromise to an excess of cardiovascular events in the general population and in those with already present atherosclerotic disease. As renal function deteriorates, certain physiologic changes occur (perhaps due to hemodynamic, inflammatory, or metabolic changes) that decrease oxygen-carrying capacity of the blood by virtue of anemia, make blood vessels stiffer by altering collagen or through medial calcinosis, raise the blood pressure, increase shearing stresses, or alter the constituents of atherosclerotic plaque or the balance of thrombogenesis and thrombolysis. At further levels of renal dysfunction, tangible metabolic perturbations are recognized as requiring specific therapy to reduce complications (such as for anemia and hyperparathyroidism), although outcome research to support some of our current guidelines is sorely lacking. Understanding the process by which renal dysfunction alters the prognosis of cardiac disease might lead to further methods of treatment. This review will outline the relationship of CKD to coronary heart disease with respect to the current understanding of the traditional and nontraditional risk factors, the role of various imaging modalities, and the impact of coronary revascularization on outcome.
Article
Although results from in vitro studies and clinical trials demonstrate strong associations between oxidative stress and cardiovascular risk, to date still no convincing data are available to suggest that treatment with antioxidants might reduce vascular events. Oxidative modifications of low-density lipoproteins (LDL) represent an early stage of atherosclerosis, and small, dense LDL are more susceptible to oxidation than larger, more buoyant particles. Oxidized LDL are independent predictors of subclinical and clinical atherosclerosis. Recent studies suggested that novel therapeutic strategies may take into account the removal of such particles from circulation. Future research is required to explore the potential synergistic impact of markers of oxidative stress and atherogenic dyslipidemia, particularly small dense LDL, on cardiovascular risk.
Article
Patients with chronic kidney disease (CKD) show a high cardiovascular morbidity and mortality. This seems to be consequence of the cardiovascular risk factor clustering in CKD patients. Non traditional risk factors such as oxidative stress and inflammation are also far more prevalent in this population than in normal subjects. Renal disease is associated with a graded increase in oxidative stress markers even in early CKD. This could be consequence of an increase in reactive oxygen species as well as a decrease in antioxidant defence. This oxidative stress can accelerate renal injury progression. Inflammatory markers such as C reactive protein and cytokines increase with renal function deterioration suggesting that CKD is a low-grade inflammatory process. In fact, inflammation facilitates renal function deterioration. Several factors can be involved in triggering the inflammatory process including oxidative stress. Statin administration is accompanied by risk reduction in all major vascular events in patients with CKD that are considered high-risk patients. These beneficial effects seem to be consequence of not only their hypolipidemic effect but especially their pleitropic actions that involve modulation of oxidative stress and inflammation.