Journal of Clinical & Translational Endocrinology 1 (2014) 108e114

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Journal of Clinical & Translational Endocrinology

journal homepage: www.elsevier.com/locate/jcte

Research Paper

Influence of aerobic exercise training on cardiovascular and

endocrine-inflammatory biomarkers in hypertensive postmenopausal
womenq
Aline P. Jarrete a, Iane P. Novais a, Hygor A. Nunes a, Guilherme M. Puga a, Maria A. Delbin b,
Angelina Zanesco a, *
a
Laboratory of Cardiovascular Physiology and Exercise Science, University of São Paulo State (UNESP), Av, 24 A, 1515, Rio Claro, SP CEP: 13506-900, Brazil
b
Department of Structural and Functional Biology, Biology Institute, UNICAMP, Campinas, SP, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Given that few studies have examined the interaction between endocrine-inflammatory mediators and
Received 20 May 2014 aerobic exercise training in hypertensive postmenopausal women, the aim of this study was to inves-
Received in revised form tigate whether aerobic exercise training (AET) for twenty-four sessions would alter cortisol, leptin and
20 June 2014
interleukin-1b (IL-1b) levels. To further analyze endothelium function in response to AET, we also
Accepted 7 July 2014
examined redox state as well as NO/cGMP pathway in this population. Eighteen hypertensive post-
menopausal women finished this study. AET program consisted of 24 sessions in treadmill, 3 times per
week, duration of 30 up to 40 min for each session, for 8 weeks at intensity of 100% of the MLSS ac-
Keywords:
Cortisol
cording to previous incremental test. Heart rate was monitored in all studied time (resting and during
Leptin exercise sessions). After 48 h of the last exercise session, blood samples were collected for biochemical
Nitric oxide pathway analyses (levels of cortisol, leptin, IL-1b, nitrite/nitrate (NOx
), cGMP, malondialdehyde (MDA) and
Blood pressure asymmetric dimethylarginine (ADMA); superoxide and catalase activity). We also measured systolic and
Redox state diastolic blood pressure. A significant reduction in body mass was observed. As expected, systolic and
diastolic blood pressure values were significantly reduced after AET in hypertensive women. We also
found a marked increase in NOx
levels as well as cGMP concentration in trained women, approximately
37.7 and 30.8%, respectively. No changes in cortisol, leptin, ADMA and IL-1b levels were observed after
AET. Similarly, MDA levels and catalase activity were not affected by AET. In contrast, a marked increase
in SOD activity was found (86.6%). In conclusion, our findings show that aerobic exercise training for
twenty-four sessions promoted a significant reduction in blood pressure by activating NO/cGMP pathway
as well as by promoting an up-regulation of SOD activity without changing in cortisol/leptin levels in
postmenopausal hypertensive women.
Ó 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Introduction phenomenon in postmenopausal women. Estrogen deficiency has

been pointed out to play a major role, but its deficiency partially
Epidemiological studies have shown that the incidence of car- explains the increased incidence of CVD since hormone replacement
diovascular diseases (CVD) in women increases dramatically after therapy did not prevent or mitigated cardiovascular events in this
menopause [1,2]. However, the underlying mechanisms are not yet population [3,4]. Oxidative stress is another explanation, where
fully clarified. Several hypotheses have been proposed to explain this increased production of the inflammatory mediators would lead to a
massive production of reactive oxygen species, which in turn,
resulting in endothelium dysfunction with decrease in nitric oxide
q This is an open access article under the CC BY-NC-ND license (http:// (NO) production or its bioavailability to the cells [5]. However, some
creativecommons.org/licenses/by-nc-nd/3.0/). studies found a positive association between CVD and inflammatory
Conflict of interest: The authors declare no conflict of interest. mediators [6e8] whereas others failed to detect any association [9]
Source of funding: Authors are grateful to Sao Paulo Research Foundation in climacteric phase. The hypothalamic-pituitary-adrenal axis has
(FAPESP): 2001/17437-7 and Coordenação de Aperfeiçoamento de Pessoal de Nível
also been linked to the higher incidence of CVD in postmenopausal
Superior (CAPES) for financial support.
* Corresponding author. Tel.: þ55 19 3526 4324; fax: þ55 19 3526 4321. women [10,11]. Nevertheless, the number of studies examining the
E-mail addresses: azanesco@rc.unesp.br, lina.co@hotmail.com (A. Zanesco). interaction between menopause status and glucocorticoids is scarce.

2214-6237/$ e see front matter Ó 2014 The Authors. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcte.2014.07.004
 A.P. Jarrete et al. / Journal of Clinical & Translational Endocrinology 1 (2014) 108e114 109

Therefore, the higher incidence of CVD in postmenopausal women each participant. After familiarization, maximal lactate steady
still a complex issue and further studies should be carried out to look state (MLSS) was defined individually for prescription of AET in-
at the insight mechanisms as well as to get more information in an tensity. Briefly, postmenopausal women performed two to five
attempt to prevent cardiovascular events in this population. On the tests with fixed duration (30 min) and walking speed (5.5 km/h)
other hand, a plethora of studies has shown that physically active on a treadmill (Movement RT 250 PRO) in accordance with pre-
subjects have more longevity with reduction of morbidity and vious study [14]. The inclination of the ergometer was used to
mortality [12,13]. Given that few studies have examined the inter- control the intensity that ranged between 1 and 15%. The intensity
action between endocrine-inflammatory mediators and aerobic ex- was adjusted in each test according to the aerobic capacity of the
ercise training in hypertensive postmenopausal women, the aim of participant. Measurement blood lactate concentration was per-
this study was to investigate whether aerobic exercise training for formed at rest, 10th and 30th min during incremental test. MLSS
twenty-four sessions would alter cortisol, leptin and interleukin-1b was determined when the difference of blood lactate concentra-
levels. To further analyze endothelium function in response to ex- tion between 10th and 30th min was not exceeded 1 mM [15].
ercise training, we also examined redox state as well as NO/cGMP AET program consisted of 24 sessions in treadmill, 3 times per
pathway in this population. week, duration of 30 up to 40 min for each session, for 8 weeks. The
intensity of the AET was 100% of the MLSS according to previous
Methodology incremental test. Heart rate was monitored and AET was supervised
by exercise physiologists in an environmental with temperature
Study participants (z25  C) and humidity (40e60%) controlled. Figure 1 illustrates the
experimental design.
This study was approved by the Ethical Committee of Institute of
Bioscience at the University of São Paulo State (UNESP). All the vol- Anthropometric parameters
unteers were recruited through advertisements in the surrounding
area of UNESP. A total of thirty-two volunteers were eligible to Body weight and height was determined using a scale and sta-
participate in the study. After all screening test, only eighteen women diometer (Toledo 2096 PP). Body mass index was calculated as the
finished the study. Postmenopausal status was determined as the ratio body weight divided by the square of the height in meters.
absence of menstruation for at least 1 year under natural or surgical Waist circumference was measured at the midpoint between the
causes were classified as hypertensive according to previous medical last rib and iliac crest.
diagnosis (systolic blood pressure: 140e159 mm Hg, diastolic blood
pressure: 90e99 mm Hg or using anti-hypertensive). The inclusion Cardiovascular parameters
criteria of this study were: to be hypertensive; body mass index
30 kg/m2; sedentary (<150 min of moderate physical activity per Blood pressure (BP) e After 20 min of sitting position, three
week or <60 min of vigorous physical activity per week). The consecutives BP measurements using a semi-automatic equipment
exclusion criteria were: smoking, taking hormone replacement (Microlife MIB-P3BTOA). Resting BP was determined as the average
therapy, diabetic, cardiovascular disease (stroke, heart failure); renal of the measurements.
dysfunction; other condition that precludes the practice of physical Heart rate (HR) e HR was measured using a heart rate monitor
exercise. Before starting the protocol, volunteers were informed (Polar FT1 TRQ) after 20 min of seated position. At the final of the
about the procedures and risks of the study and signed a consent resting period the value of HR was obtained.
form in accordance with Ethical Committee of UNESP.
Blood samples
Study protocol
Blood samples were collected after 12 h of overnight fast
This clinical trial lasted 10 weeks and all parameters were (between 7:00 and 8:00 am). Blood samples were collected from
evaluated at initial time and after 24 sessions of the aerobic ex- the antecubital vein using standard venipuncture methods.
ercise training (AET). Initially, the anthropometric and cardio- Samples were centrifuged (3000 rpm, 12 min) and the superna-
vascular parameters were measured and volunteers were tant (plasma and serum) were stored in aliquots at
80  C for
familiarized to the treadmill during 2e4 days, depending upon future analysis.

Figure 1. Experimental design.

110 A.P. Jarrete et al. / Journal of Clinical & Translational Endocrinology 1 (2014) 108e114

Table 1 Results
Effects of aerobic exercise training on anthropometrical parameters, lipid profile,
glycemia and MLSS in hypertensive postmenopausal women.
Body mass index values were significantly reduced in hyperten-
Parameters (n ¼ 18) Initial Final sive postmenopausal women after 24 sessions of AET approximately
Age (yrs) 58.3  1.2 e 1.5% as compared to initial time. However, no changes were found in
Time after menopause (yrs) 10.3  2.1 e waist circumference, lipid profile and glycemia. On the other hand,
BMI 27.3  0.5 26.9  0.5* the intensity of physical exercise employed in our study was effective
WC 94.4  1.6 93.4  1.5*
to promote a significant increase in MLSS after AET, approximately
TC (mg/dL) 195.4  6.4 194.1  5.5
LDL-c (mg/dL) 124.7  6.4 124.2  5.0 32.7%. Data are summarized in Table 1. Regarding antihypertensive
HDL-c (mg/dL) 46.9  1.7 49.1  1.5 therapy, 67% of the participants were on renin-angiotensin inhibitors
VLDL-c (mg/dL) 23.8  1.9 20.6  1.5 or AT1 receptor blockers whereas six volunteers were on diuretics or
TG (mg/dL) 113.8  10 103.1  7.8
beta-adrenergic receptor blocker therapy (33%). Regarding hypo-
Glycemia (mg/dL) 87.2  2.2 90.3  2.1
Rest HR 67.3  2.7 64.7  2.2*
lipidemic compound, 50% of the volunteers were on therapy previ-
MLSS exercise HR 152  4.7 151  5.1 ously to the study.
MLSS threshold 5.5  0.4 7.3  0.5* As expected, AET was effective in lowering arterial blood pres-
BMI ¼ body mass index (kg/m2); WC ¼ waist circumference (cm); TC ¼ total sure in trained HT women, approximately
3.8% and
5.9% for
cholesterol; LDL ¼ low density lipoprotein; HDL ¼ high-density lipoprotein; systolic and diastolic blood pressure, respectively (Figure 2, panels
VLDL ¼ very low-density lipoprotein; TG ¼ triglycerides. HR ¼ heart rate (bpm); A and B). Resting heart rate values were also decreased after 24
MLSS ¼ maximal lactate steady state; Data are mean  SEM.
*P < 0.05 compared with initial time.

Biochemical analyses

Lipid profile and glycemia e Serum concentrations of total

cholesterol, low-density lipoprotein-cholesterol, very low-density
lipoprotein cholesterol, high-density lipoprotein cholesterol, tri-
glycerides and glycemia were determined using automated standard
method (Cobas Mira Plus).
Cortisol e Serum concentrations of cortisol were measured by
the chemiluminescence (ADVIA CentaurÒ). This is a competitive
immunoassay that uses direct chemiluminescent technology.
Leptin e Serum leptin concentrations were measured by ELISA
using a commercial available kit (SPI Bio, Montigny-le-Bretonneux,
France) according to the manufacturer’s instructions.
Interleukin-1b (IL-1b) and guanosine cyclic monophosphate
(cGMP) e Plasma concentrations of IL-1b and cGMP were measured
by ELISA using a commercial available kit (R&D Systems, Mine-
apolis, MN, USA) according to the manufacturer’s instructions.
Asymmetric dimethylarginine (ADMA) e Plasma concentrations of
ADMA were measured by ELISA using a commercial available kit
(Immunodiagnostik AG, Bensheim, Germany) according to the man-
ufacturer’s instructions.
Nitrite/Nitrate (NO
x ) e Plasma concentrations of NOx were

measured to evaluate NO production by commercial available kit

(Cayman Chemical, Ann Arbor, MI, USA) according to the manufac-
turer’s instructions. Before starting this assay samples were ultra-
filtered through micro filter (Microcon Centrifugal Filter Units,
10 kDa, Millipore, Bedford, MA).
Superoxide dismutase (SOD), catalase and malondialdehyde (MDA) e
All these markers were measured by ELISA using a commercial avail-
able kit (Cayman Chemical, Ann Arbor, MI, USA) according to the
manufacturer’s instructions. SOD’s assay detects radicals superoxide
generated by xanthine oxidase and hypoxanthine, revealing the plas-
matic activity of this enzyme. Catalase’s assay is based on the reaction
of the enzyme with methanol in an optimal H2O2 concentration. Serum
levels of MDA were determined to evaluate lipid peroxidation [16].

Statistical analysis

Data are presented as mean  standard error mean. Normality of

the data was verified by the KolmogoroveSmirnov’s test. A paired
Figure 2. Effects of aerobic exercise training on systolic blood pressure (SBP, panel A),
Student’s t-test was used to analyze the effect of AET on the car- diastolic blood pressure (DBP, panel B) and resting heart rate (HR, panel C) in post-
diometabolic and endocrine parameters. For all analyses, P < 0.05 menopausal hypertensive women (n ¼ 18). *P < 0.05 paired t test between initial and
was considered statistically significant. final time of the study.
 A.P. Jarrete et al. / Journal of Clinical & Translational Endocrinology 1 (2014) 108e114 111

pressure values and cortisol levels at initial time of the study

(r2 ¼ 0.2422, P < 0.0448, n ¼ 17, Figure 6A) whereas this correlation
was abrogated after AET (P > 0.05, Figure 6B).

Discussion

A number of studies have shown that cardiovascular diseases can

be prevented by regular physical exercise either in human or in
laboratory animals, which is strongly associated with an increase in
NO bioavailability [17e19]. Regarding postmenopausal women,
recent study found that aerobic exercise training even in a low in-
tensity promoted reductions in blood pressure showing how
changing in the lifestyle is favorable for this particular population in
preventing cardiovascular events [20]. However, no mechanist

Figure 3. Effects of aerobic exercise training on NOx
(panel A), cGMP (panel B) and
ADMA (panel C) levels in postmenopausal hypertensive women (n ¼ 18). *P < 0.05
paired t test between initial and final time of the study.

sessions of aerobic physical exercise (Table 1 and Figure 2C). Given

that it is well established that the health beneficial effect of the ex-
ercise training is related to activation of NO/cGMP signaling pathway,
we have evaluated these biomarkers before and after twenty-four
sessions of aerobic physical exercise. We found a marked increase
in NOx
levels, which reflect NO production, as well as cGMP con-
centration in trained women, approximately 37.7 and 30.8%,
respectively (Figure 3, panels A and B). Interestingly, we found no
changes in ADMA levels (Figure 3C).
Furthermore, we also analyzed the redox state by measuring SOD
and catalase activities and MDA concentration. Our findings show
that AET promoted a profound increase in SOD activity, approxi-
mately 86.6% (Figure 4A). No changes were found catalase activity
and MDA concentration (Figure 4, panels B and C).
Regarding endocrine-inflammatory mediators, we found no ef-
fects of the AET on cortisol, leptin and IL-1b levels in postmenopausal Figure 4. Effects of aerobic exercise training on SOD (panel A), catalase (panel B) ac-
hypertensive women (Figure 5, panels A, B and C, respectively). tivity and MDA concentration (panel C) in postmenopausal hypertensive women
Interestingly, we found a positive relationship between systolic blood (n ¼ 18). *P < 0.05 paired t test between initial and final time of the study.
112 A.P. Jarrete et al. / Journal of Clinical & Translational Endocrinology 1 (2014) 108e114

inhibition and hypertension in postmenopausal women, we looked

at ADMA levels since evidences have linked increased ADMA levels
in patients with angina, arterial hypertension and immune
dysfunction mainly in elderly and postmenopausal women [25e27].
We found no changes in ADMA levels in trained women excluding
the contribution of this endothelial pathway on the beneficial effects
of exercise training in blood pressure regulation. In contrast, two
recent studies from the same group showed a decrease in plasma
ADMA in healthy postmenopausal women in response to aerobic
exercise training as well as an inverse relationship between aerobic
fitness and levels of ADMA [28,29]. However, these studies did not
measure NO production, and blood pressure values were not
modified by exercise training. Thus, more studies should be carried
out to check the contribution of the endogenous inhibition of NO
availability on arterial hypertension as well as the effects of exercise
training on ADMA/NOS pathway.
Increased oxidative stress has been pointed out to play an
important in the pathogenesis of arterial hypertension in men [30]
as well as in postmenopausal women [5,31]. Although evidences
have demonstrated that trained [32] or physically active healthy
postmenopausal women [33] showed a decreased in circulating
concentrations of MDA as compared to sedentary one, no blood
pressure measurements were performed in these studies. Thus, the
data do not clarify the high incidence of arterial hypertension in
postmenopausal women or explain the insight mechanisms in the
phenomenon. In our study, we found no changes in MDA levels in
response to exercise training in hypertensive postmenopausal
women excluding the contribution of this biomarker in the bene-
ficial effects of physical exercise on blood pressure regulation. We
also found no changes in the pro-inflammatory mediators, IL-1b
and leptin, in response to exercise training. It has been reported the
influence of estrogen on pro- and anti-inflammatory pathway in
different cells types [34]. Indeed, in whole human blood cultures,
the addition of different concentration of estrogen decreases
secretion of several pro-inflammatory mediators, mainly IL-1b [35].
Additionally, it has been demonstrated an increase in inflammatory
mediators in experimental model of menopause [36]. Interestingly,
a previous study showed that IL-1b levels increase in the early stage
of the menopause (less than five years) and return to the normal
levels in the late stage, with values similar to premenopause phase
[8]. Thus, it is not clear whether estrogen deficiency could lead to an
inflammatory state in postmenopausal women. Furthermore, the
range of concentration of IL-1b levels in women is very wide
varying between 0.30 and 0.081 pg/mL depending on the repro-
ductive phase or not as well as the time after menopause [37].
Regarding leptin levels and postmenopausal women, the interac-
Figure 5. Effects of aerobic exercise training on cortisol (panel A), leptin (panel B) and tion is even more complex [38]. An increase [39], no variation [40]
IL-1b levels (panel C) in postmenopausal hypertensive women (n ¼ 18). *P < 0.05 and a decrease [41,42] in circulating leptin levels were detected
paired t test between initial and final time of the study.
after menopause. Previous studies reported that postmenopausal
women under caloric restriction [43] or on tibolone therapy [42]
events have been reported. Thus, one of the objectives of our study is showed a significant reduction in leptin levels. In our study, exer-
to examine different pathways that regulate blood pressure in cise training did not affect leptin levels even though there was a
response to exercise training in hypertensive postmenopausal slight reduction in the BMI (1.5%). Indeed, previous studies have
women. We found that twenty-four sessions of aerobic physical shown that changes in leptin levels are detected only when physical
exercise was effective in reducing BMI as well as to improve the training is associated with caloric restriction in postmenopausal
physical capacity of all volunteers. Additionally, the reductions of women [44,45].
systolic and diastolic blood pressure were positively associated with A number of studies have shown the importance of cortisol, the
an improvement of NO/cGMP pathway as well as an up-regulation of major glucocorticoid hormone produced in human, in elevating
SOD activity. Taken together, these findings show that aerobic ex- blood pressure [46e48]. Several signaling pathways seem to be
ercise training promoted an improvement of endothelium function involved in the mechanisms by which cortisol produces arterial hy-
in hypertensive postmenopausal women. Indeed, previous studies pertension including sodium/volume homeostasis, activation of the
from our group have systematically demonstrated the beneficial renin-angiotensin system, and increased sympathetic drive [49e52].
effects of the exercise training on cardiovascular system by increased Additionally, it has been reported that cortisol impairs NO production
production of NO and/or its bioavailability in postmenopausal measured by NOx
levels attributing thus, the cortisol-induced hy-
women [21e24]. To further examine the association between NO pertension to the NO deficiency in both human and experimental
 A.P. Jarrete et al. / Journal of Clinical & Translational Endocrinology 1 (2014) 108e114 113

A B
r 2 = 0.242 r 2 = 0.007
P = 0.044 P = 0.741

Figure 6. Correlation between systolic blood pressure values and cortisol levels at initial time (panel A) and after twenty-four sessions (panel B) of physical exercise in post-
menopausal hypertensive women.

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