Effects of Aerobic Exercise on Atherosclerotic Risk in Postmenopausal Women
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To study the effects of aerobic exercise on lipid metabolism, endothelial function, and oxidative stress reaction in postmenopausal women, in order to prevent and control atherosclerosis.
Thirty-two women with natural menopause were randomly divided into an exercise group and a control group. Participants in the exercise group (n = 16) took part in a 3-month aerobic training program according to their exercise prescription, while participants in the control group (n = 16) maintained their usual lifestyles. Lipids, endothelial function, and oxidative stress-related indicators were measured before and after the intervention.
After 3 months of aerobic training at an intensity of 50–60% of cardiorespiratory fitness, serum total cholesterol and low-density lipoprotein cholesterol decreased significantly (P < 0.05), and high-density lipoprotein cholesterol increased significantly (P < 0.01). A significant reduction in endothelin (P < 0.01) and a significant increase in nitric oxide (P < 0.05) were also observed. The training intervention also delayed the increase in homocysteine and cysteine aspartate-specific protease-3 in postmenopausal women.
Aerobic exercise had a positive effect on blood lipids, endothelial function, and oxidative stress of postmenopausal women, and these changes may mitigate the risk of atherosclerosis occurrence. Similar exercise programs could be used as a primary atherosclerosis prevention strategy for postmenopausal women.
KeywordsAerobic exercise Postmenopausal women Atherosclerosis Endothelial function Oxidative stress
Atherosclerosis (AS) has a complicated pathogenesis and dyslipidemia is a key risk factor. In addition, endothelial dysfunction (ED) is considered as an early pathological change of atherosclerosis, which is an independent risk factor for cardiovascular diseases (CVD) in postmenopausal women [4, 31, 33]. Extremely high levels of oxidative stress in the body can result in damage to the vascular endothelial cells (VEC) and inhibition of endothelial function . Oxidized low-density lipoprotein (ox-LDL) occurs within the vascular wall due to oxidative stress reactions, and ox-LDL is one of the main causes of the occurrence and progression of atherosclerosis .
Menopause is an important transition in a woman’s life, and the incidence of atherosclerosis in postmenopausal women is significantly higher than in premenopausal women. Previous studies have shown progressive attenuation of endothelial function, elevation of arterial stiffness, and abnormal blood lipids in the menopausal transition and postmenopause [15, 27, 40]. In addition, higher levels of oxidative stress were observed in postmenopausal women compared with premenopausal women [26, 37].
Studies have shown that aerobic exercise can improve cardiovascular system function and play a positive role in the prevention and treatment of atherosclerosis [9, 24, 28, 46]. However, few studies have focused on the preventive effect of aerobic exercise on atherosclerosis in postmenopausal women, especially through endothelial function and oxidative stress-related indicators; exercise is associated with improvement in endothelial function, whereas the efficacy of exercise to improve endothelial function in postmenopausal women is equivocal [35, 36, 45]. Few studies in China have examined atherosclerosis in postmenopausal women, and guidelines for preventing it have not been developed for Chinese women.
Therefore, the primary purpose of this study was to determine the effects of aerobic exercise on lipid metabolism, endothelial function, and oxidative stress reactions in postmenopausal women, and to increase the body of knowledge on prevention of atherosclerosis in this population.
Postmenopausal women (50–70 years old) participated in the study. Participants were recruited among women with natural menopause for more than 1 year. Participants were excluded from the current study if they had an orthopedic or other condition that limited participation in daily exercise; had a history of myocardial infarction, stroke, diabetes mellitus, chronic respiratory disease or cancer; took hormones or medications, such as anti-inflammatory drugs, hypoglycemic drugs, antihypertensive drugs, or lipid-lowering drugs; or had an ovarian or uterine ablation. Furthermore, we excluded participants who answered “Yes” to the question “smoking or alcohol drinking regularly”, those with abnormal electrocardiogram (ECG) responses consisting of ischemic ST-T wave abnormalities and rhythm and conduction disturbances, and those who participated in regular exercise (≥ three 30-min moderate exercise sessions/week, for more than 3 months).The exclusion criteria were used to decrease potential biases due to pre-existing diseases or exercise habits, which might affect changes in cardiorespiratory fitness and biochemical indices of atherosclerosis risk. The study protocol was reviewed and approved by the IRB at Beijing Sport University, and all participants provided written informed consent.
At baseline, all participants completed a structured questionnaire, which included questions about personal health histories, use of medication, family medical history, alcohol drinking habits, smoking habits, physical activity habits, and sociodemographic information.
Blood samples were obtained from participants after an overnight fast (12 h) at baseline and after a 3-month follow-up. Blood parameters were analyzed at a certified laboratory using the standard methods and quality control procedures. The serum total cholesterol (TC) and triglyceride (TG) levels were analyzed by enzymatic methods, and serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were determined by direct methods (Sekisui Medical CO., LTD., Japan). The serum nitric oxide (NO) concentration was analyzed using the nitrate reductase method (NO assay kit, Nanjing Jiancheng Bioengineering Institute, China), and serum endothelin (ET) concentration was measured by radioimmunoassay method (ET assay kit, Beijing North Bioengineering Institute, China). The serum level of homocysteine (Hcy) was assessed by enzymatic cycling method (Hcy assay kit, Beijing Jiuzhou Taikang Biotechnology Co., Ltd., China), and serum level of cysteine aspartate-specific protease-3 (caspase-3) was measured using the ELISA method (Human Caspase 3 ELISA Kit, Beijing Dongfang Tuojin Technology Co., Ltd., China).
Body mass and height were determined by a standard clinical stadiometer and scale, with light clothing but without shoes. Resting ECG was conducted according to a standard manual of operations. Seated resting blood pressure (BP) was measured using a mercury sphygmomanometer with standard auscultation method.
Cardiorespiratory Fitness (CRF)
CRF was determined by a maximal exercise test at 60 rpm on the cycle ergometer. Participants started the test with a workload of 30 W lasting 3 min. Then, the workload was increased by 15 W every 3 min until test termination. All participants were encouraged to give maximal effort during the test. Energy metabolism was assessed by Cortex MetaMax 3B portable gas metabolic analyzer (a breath-by-breath gas analysis system), and ECG and BP were measured using dynamic electrocardiographic (ECG) monitoring and dynamic sphygmomanometer.
CRF in maximal METs (Metabolic Equivalent of Energy) was calculated from the final workload using the following formula from the American College of Sports Medicine (ACSM): [7.0 + (1.8 × work rate)/body mass]/3.5 . Each participant’s exercise prescription was then based on her workload.
Following the baseline test, all participants were randomly assigned to the exercise group (EX) (n = 18) or the control group (CON) (n = 18), using a random number table. The EX group underwent a 3-month aerobic exercise intervention, while members of the CON group maintained their regular lifestyles during this period. Four participants, two from each of the EX and CON groups, quit the study. Therefore, complete data were available for 32 participants.
During the 3-month study, participants in the CON group were asked to maintain their usual activity levels; they were offered a postponed exercise program with supervision after the 3-month intervention period. Participants in the EX group completed 3 months of aerobic exercise training, at heart rates corresponding to 50–60% of cardiorespiratory fitness (50–60% CRF), 5 times a week. The exercise training consisted of walking, which was carried out on a ground track field. Polar heart rate monitors were used to help participants maintain their target heart rates. The duration on day 1 was 30 min, and it was increased by 5 min each day until participants were walking for 60 min (week 2). It remained at 60 min during the study. The aerobic exercise session was preceded by 5–10 min of light stretching.
Exercise was supervised by researchers 5 times per week during the first 2 weeks, twice per week from the third week to one and a half months, and once per week from one and a half months to 3 months. Research staff supervised, instructed, and advocated for all participants, to ensure adherence to the program.
Statistical analyses were performed with the SPSS software. All data were expressed as means ± SD. After normal distribution test and homogeneity test of variance, the differences between baseline and post-exercise intervention were examined using paired t tests, and the differences between the CON and EX groups were examined using Student’s t test. Values of P < 0.05 were considered statistically significant.
Basic Information and Baseline Data
Basic characteristics and baseline data of participants
CON (n = 16)
EX (n = 16)
60.25 ± 3.72
61.38 ± 5.90
157.29 ± 5.09
158.79 ± 5.69
61.27 ± 7.81
59.74 ± 6.71
Menopause period (year)
10.00 ± 5.22
10.81 ± 5.75
74.19 ± 7.55
68.75 ± 7.90
120.00 ± 15.97
125.00 ± 19.79
75.13 ± 7.12
73.75 ± 10.17
6.33 ± 1.24
5.94 ± 1.40
5.70 ± 0.67
5.96 ± 0.60
1.37 ± 0.56
1.31 ± 0.66
1.51 ± 0.31
1.54 ± 0.32
3.26 ± 0.82
3.50 ± 0.47
16.23 ± 14.48
15.78 ± 10.40
47.84 ± 27.90
58.54 ± 31.19
8.79 ± 2.94
10.51 ± 4.42
363.35 ± 79.70
402.98 ± 92.95
4.19 ± 0.73
4.42 ± 0.56
Changes in Lipid Metabolism
After 3 months, the EX group demonstrated significantly increased serum levels of HDL-C (0.08 mmol/L, P < 0.01), whereas the CON group demonstrated nonsignificantly reduced serum levels of HDL-C (P > 0.05). In addition, serum levels of HDL-C in the EX group were significantly higher than those of the CON group; the mean difference was + 0.28 mmol/L (P < 0.05). There were significant differences in changes in serum HDL-C between EX and CON groups (P < 0.05).
After 3 months, serum TG concentration decreased in participants in the EX group (P > 0.05), but increased significantly in participants in the CON group (0.37 mmol/L, P < 0.05). Moreover, serum TG levels in the EX group were significantly lower than those of the CON group (− 0.57 mmol/L, P < 0.01). There were significant differences in changes in serum TG between the EX and CON groups (P < 0.01).
Changes in AI and Body Weight
After 3 months, the EX group demonstrated significantly decreased AI (0.44, P < 0.01), but the CON group demonstrated significantly increased AI (0.47, P < 0.05). Furthermore, AI in the EX group was significantly lower than that of the CON group; the mean difference was − 0.8 (P < 0.01). There were significant differences in changes in AI between the EX and CON groups (P < 0.01).
Changes in Vascular Endothelial Function
After 3 months, serum nitric oxide was significantly increased in the EX participants (14.55 μmol/L, P < 0.05), but remained unchanged in the CON participants.
Changes in Oxidative Stress Reaction
Changes in Cardiovascular Function
Participants undergoing the 3-month exercise intervention had a significant increase in CRF (0.49 METs, P < 0.05), while participants in the CON group had a nonsignifcant reduction in CRF (P > 0.05). Moreover, CRF in the EX group was significantly higher than that of the CON group (0.41 METs, P < 0.01).
Gender differences exist in the incidence of atherosclerosis with aging. Studies have shown that the incidence of atherosclerosis in premenopausal women is lower than in men at the same age . However, the incidence of atherosclerosis increases significantly after menopause; it is more than 4 times higher than in premenopausal women and exceeds that of men. However, a survey conducted by the American Heart Association (AHA)  showed that only 21% of women are aware that atherosclerosis and subsequent CVD are the main threats to their health; most women have a low awareness of the severity of atherosclerosis and do not have a clear idea of how to prevent and treat it.
The present study investigated the effects of aerobic exercise training on multiple risk factors, including blood lipids, NO, ET, Hcy, and caspase-3 in postmenopausal women at high risk of atherosclerosis. All of the women in the study also had borderline dyslipidemia. There are three main findings from the current study. First, 3-month aerobic training at the intensity of 50–60% CRF significantly decreased TC and LDL-C, and increased HDL-C in postmenopausal women. Second, postmenopausal women who participated in 3 months of aerobic training showed a significant reduction in serum ET and significant increase in serum NO. Third, aerobic training can delay the increase in homocysteine and cysteine aspartate-specific protease-3 in postmenopausal women. We believe that this is the first study to examine the effects of aerobic exercise on the atherosclerosis risk of postmenopausal women, with the combination of blood lipids, endothelial function, and oxidative stress reaction.
Effect of Exercise Intervention on Lipid Metabolism and AI in Postmenopausal Women
The key pathogenesis of atherosclerosis is dyslipidemia. The high levels of low-density lipoprotein (LDL) and ox-LDL are the primary risk factors related to atherosclerosis. In addition, high concentration of TG also promotes formation of ox-LDL, which later triggers atherosclerosis. According to the inter-heart studies, menopause may cause adverse changes in the types and concentrations of lipoprotein in women. Therefore, the correlation between dyslipidemia and atherosclerosis in postmenopausal women is higher than in men [47, 48]. In this study, serum levels of TC and LDL-C in all participants were higher than normal. It has been reported that LDL-C or TC was independent predictors of risk for atherosclerotic cardiovascular disease (ASCVD) .
After the 3-month exercise intervention, the serum TC concentration in the EX group decreased significantly, from 5.96 to 5.57 mmol/L (6.5%, P < 0.01). However, the serum TC concentration in the CON group increased significantly, from 5.70 to 5.97 mmol/L (P < 0.05). It has been reported that the risk of coronary heart disease (CHD) decreases 2–3% for every 1% drop in serum level of TC [18, 41]. Therefore, we can speculate that, after aerobic training, the risk of CHD will be reduced by 13–20% in the EX group.
In addition, participants who underwent the exercise intervention experienced a significant reduction in serum levels of LDL-C (3.50 vs. 3.20 mmol/L, P < 0.05). Nevertheless, the serum levels of LDL-C in the CON group increased significantly (3.26 vs. 3.64 mmol/L, P < 0.01). Studies have shown that, for each 1 mg/dL (0.026 mmol/L) drop in LDL-C, there is a 1–2% decrease in CHD risk . Based on these values, we can speculate that the CHD risk will be diminished by 11–23% in the EX group after aerobic training.
In addition, studies have shown that, for women, each 1 mg/dL (0.026 mmol/L) increment in HDL-C is associated with a 3% decrement in CHD risk and 3.7% decrement in CVD mortality . In the current study, after a 3-month exercise intervention, the serum levels of HDL-C in the EX group increased significantly, from 1.54 to 1.62 mmol/L (P < 0.01). Moreover, postmenopausal women are more likely to suffer metabolic syndrome when their HDL-C concentration is lower than 1.295 mmol/L . In this study, HDL-C values showed a downward trend in the CON group. During the follow-up period, serum HDL-C concentration of 4 participants in the CON group decreased to lower than 1.295 mmol/L.
The serum TG concentration in the EX group decreased after the 3-month exercise intervention, and was significantly lower than that of the CON group (− 0.57 mmol/L, P < 0.01). Participants in the CON group experienced a significant increase in serum TG concentration (3.50 vs. 3.20 mmol/L, P < 0.05). The slight increase in serum TG may be primarily due to the increment of very low-density lipoprotein (VLDL) and its residual particles. VLDL and its residual particles may be the direct causative factors of atherosclerosis because of their small size. The higher level of TG may induce atherosclerosis by changing the structure of LDL and HDL . TG is the most abundant lipid in the human body, and it can be oxidized and decomposed through a series of chemical reactions to provide energy for people during exercise . It is also the mechanism through which exercise training can regulate blood lipids.
AI not only reflects the disorder of lipid metabolism in the human body, but also can be used for evaluating the severity of coronary artery disease, which is a risk factor for atherosclerosis . The higher the AI, the greater the risk for atherosclerosis . In this study, after the 3-month exercise intervention, AI in the EX group decreased significantly (3.01 vs. 2.57, P < 0.01), and was significantly lower than that of the CON group (− 0.8, P < 0.01). Participants in the CON group experienced a significant increase in AI (2.90 vs. 3.37, P < 0.05).
In addition, CRF in the EX group increased significantly after the 3-month exercise intervention (5.94 vs. 6.43 METs, P < 0.05), and was significantly higher than that of the CON group (+ 0.41 METs, P < 0.01).
These results suggest that the 3-month aerobic training in the postmenopausal women produced favorable physiological effects, which may reduce the risk of atherosclerosis.
Effect of Exercise Intervention on Endothelial Function in Postmenopausal Women
Vascular endothelial cells secrete nitric oxide (NO) and endothelin (ET). NO is a potent vasodilator substance and is thought to have anti-atherosclerotic properties . ET is a vasoconstrictor substance. Therefore, it has been proposed that the interaction between NO and ET may be useful to maintain proper function of vascular endothelial cells and prevent atherosclerosis. The alteration of endothelial function associated with dyslipidemia may break the original balance [17, 29], induce endothelial dysfunction, and promote the occurrence and progression of atherosclerosis . Before menopause, the endothelial progenitor cells (EPCs) are functionally active, and they can enhance endothelial repair and regeneration. The changes of functional state of EPCs are not only a characteristic of menopause, but are also associated with endothelial inflammation [7, 43].
In a study conducted by Maeda et al. , eight healthy young subjects (20.3 ± 0.5 years old) followed a training program consisting of three-to-four 60-min sessions/week on a cycle ergometer (70% VO2max). After 8 weeks, plasma levels of NO increased significantly (20.69 ± 3.20 vs. 38.64 ± 8.16 μmol/L, P < 0.05) and plasma levels of ET decreased significantly (1.65 ± 0.14 vs. 1.23 ± 0.12 pg/mL, P < 0.05). These changes lasted for at least 1 month after the cessation of exercise training, which suggests that aerobic training improves endothelial function and helps prevent atherosclerosis. Recently, Bailey et al.  examined whether prior aerobic exercise could attenuate endothelial dysfunction induced by a high-sugar meal in postmenopausal women. The results showed that there were no significant changes in ET and NO in postmenopausal women after a 60-min bout of aerobic exercise at 75% of the age-predicted maximal heart rate (13–16 h before high-sugar meal). They concluded that one-time aerobic exercise before high-sugar diet did not have the effect of reducing endothelial dysfunction.
In those previous studies, the intensity used in exercise training was relatively high, and there was no study that investigated whether long-term regular aerobic exercise could improve endothelial function in postmenopausal women with borderline dyslipidemia. The novel finding of this current study is that 3 months of aerobic training at an intensity of 50–60% CRF (five 60-min sessions/week) is associated with an altered endothelial functional in this population.
Effect of Exercise Intervention on Oxidative Stress in Postmenopausal Women
Imbalance of oxygen free radicals in the body can result in the chain reaction of phospholipid membrane and forming lipid peroxide, which can cause oxidative stress damage. Homocysteine (Hcy) is capable of self-oxidation in the cell through the sulfhydryl group, which induces the oxidative stress reaction. High levels of Hcy will increase oxidative stress responses, result in accumulation of large amounts of reactive oxygen species (ROS), and elicit the peroxidation of phospholipids, lipoproteins, and LDL . In addition, high concentration of Hcy can also inhibit the activity of antioxidant enzymes, impair the function and structure of endothelial cells, induce endothelial dysfunction, promote the occurrence and development of atherosclerosis, and play an important role in the whole process of atherosclerosis [3, 16]. There is a gender difference in serum Hcy level, and the serum Hcy level of premenopausal women is lower than that of postmenopausal women, which may be related to the regulation of estrogen metabolism. The low level of Hcy in premenopausal women is one of the positive factors for the prevention of atherosclerosis.
However, few studies have examined the influence of exercise on Hcy. Currently, no consensus exists on which kind of exercise and what intensity of the exercise should be performed to decrease Hcy. The results of 16-week animal experiments showed that moderate- and high-intensity exercise could effectively reduce the serum Hcy concentration of hyperhomocysteinemia (HHcy) rats, and the high-intensity group had the lowest level of Hcy, which suggested that Hcy may be sensitive to high-intensity exercise .
Normal reference values of fasting serum Hcy concentration in adults are 5–15 μmol/L . There were no significant differences between serum Hcy levels of participants in this study and normal reference values before and after the intervention, and there were no significant differences between the EX and CON groups. After the 3-month intervention, serum level of Hcy in the EX group decreased slightly (− 0.3 μmol/L), while the level in the CON group increased from 8.79 μmol/L at baseline to 9.16 μmol/L. This finding indicates that the aerobic exercise prescription used in this study can ameliorate the Hcy level in postmenopausal women to some extent. The results also suggested that, for postmenopausal women without HHcy, it may take longer for aerobic training to induce changes of Hcy.
Cysteine aspartate-specific protease-3 (caspase-3) is a polypeptide consisting of 277 amino acids and participates in the process of lipid peroxidation in the body. It is considered one of the most important proteases that cause oxidative damage to the ovaries . Under normal physiological conditions, the levels of antioxidant enzymes such as superoxide dismutase (SOD) are negatively correlated with malondialdehyde (MDA) and caspase-3 levels, and they are in dynamic equilibrium. During oxidative stress, activities of antioxidant enzymes are inhibited, and caspase-3 is activated by intracellular superoxide. Recently, some studies have found that caspase-3 plays an important role in the occurrence and development of atherosclerosis and may be the main influencing factor in the instability of atheromatous plaque . Unstable plaque is vulnerable and prone to rupture and shedding, and it can clog blood vessels and result in embolism, which is an important risk factor for cardiovascular disease . From this perspective, unstable plaque in some cases may be more dangerous than the arterial stenosis induced by atherosclerosis.
Matulevicius et al.  analyzed the plasma caspase-3 concentration of 3221 subjects in 2008, which was the first study to examine the relationship between human plasma caspase-3 level and atherosclerosis. They found that caspase-3 level was associated with atherosclerosis. Those subjects with elevated plasma caspase-3 generally showed increases in the degree of coronary artery calcification and aortic wall thickening. Other studies have shown that caspase-3 activated by superoxide could accelerate the apoptosis of vascular smooth muscle cells, impair endothelial cells , and promote the instability of atherosclerotic plaques . As a risk factor of atherosclerosis, serum caspase-3 has received increasing attention by scholars in recent years; however, little attention has been paid to the effect of aerobic exercise on serum caspase-3 level in postmenopausal women. In this study, after the 3-month aerobic exercise training, we did not observe a significant reduction in serum caspase-3 concentration in the EX group, although a longer exercise period may result in significant changes. Because the current study was the first to analyze the change in serum caspase-3 level in postmenopausal women with borderline dyslipidemia after exercise intervention, we could not compare our results with others. Additional studies in more diverse population samples of women and men are needed to better understand this mechanism.
To our knowledge, this was the first study to examine the effect of aerobic training on the atherosclerosis risk of postmenopausal women by examining a combination of blood lipids, endothelial function, and oxidative stress reaction. In addition, this study was first of its kind to discuss the influence of aerobic exercise on serum Hcy and caspase-3, and their role in preventing atherosclerosis, in postmenopausal women. Another strength of this study was that CRF was determined by a standardized exercise test on the cycle ergometer in the laboratory, and individual exercise prescription was based on it.
This study also has some limitations. We did not have sufficient data about daily food intake of participants. However, we did conduct 3-day food records before and at the end of the intervention, and the results showed that there was no significant difference in intake of energy, protein, carbohydrate, and lipids (data not shown). Another limitation of the study was that all participants were postmenopausal women with borderline dyslipidemia, so these findings may not be extended to people with cardiovascular diseases.
In conclusion, 3 months of aerobic exercise had a positive effect on blood lipids, endothelial function, and oxidative stress of postmenopausal women, and these changes may mitigate the risk of atherosclerosis occurrence. The findings suggest that postmenopausal women with borderline dyslipidemia or endothelial dysfunction can use this exercise prescription, exercising 5 or more times per week, for the prevention of atherosclerosis and cardiovascular diseases.
This work was supported by the General Administration of Sport of China (2017B064) and Beijing Sport University (2018GJ014). The authors sincerely thank all of the women who participated in the study and Gaye Groover Christmus, MPH for editorial assistance in the development of the manuscript.
Compliance with ethical standards
Conflicts of interest
The authors declare no conflicts of interest.
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