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Elevated pentraxin 3 level at the early stage of exercise training is associated with reduction of arterial stiffness in middle-aged and older adults

Abstract

Regular exercise improves aging-induced deterioration of arterial stiffness, and is associated with elevated production of pentraxin 3 (PTX3) and anti-inflammatory as well as anti-atherosclerotic effects. However, the time-dependent effect of exercise training on arterial stiffness and PTX3 production remains unclear. The purpose of this study was to investigate the time course of the association between the effects of training on the circulating PTX3 level and arterial stiffness in middle-aged and older adults. Thirty-two healthy Japanese subjects (66.2±1.3 year) were randomly divided into two groups: training (exercise intervention) and sedentary controls. Subjects in the training group completed 8 weeks of aerobic exercise training (60–70% peak oxygen uptake (VO2peak) for 45 min, 3 days per week); during the training period, we evaluated plasma PTX3 concentration and carotid–femoral pulse wave velocity (cfPWV) every 2 wk. cfPWV gradually declined over the 8-week training period, and was significantly reduced after 6 and 8 week of exercise intervention (P<0.05). Plasma PTX3 level was significantly increased after 4 weeks of the intervention (P<0.05). In addition, the exercise training–induced reduction in cfPWV was negatively correlated with the percent change in plasma PTX3 level after 6 week (r=−0.54, P<0.05) and 8 weeks (r=−0.51, P<0.05) of the intervention, but not correlated at 4 weeks. Plasma PTX3 level was elevated at the early stage of the exercise training intervention, and was subsequently associated with training-induced alteration of arterial stiffness in middle-aged and older adults.

Introduction

Cardiovascular diseases are the leading cause of death, and arterial stiffness is a predictor of cardiovascular diseases.1 Increased central arterial stiffness due to aging and/or physical inactivity causes impairment of the conduit and buffering functions of arteries, leading to several pathological conditions, including hypertension, atherosclerosis, congestive heart failure, stroke and aortic root regurgitation.2, 3, 4, 5 Several studies have shown that aerobic exercise training reduces the arterial stiffness that occurs with advancing age.6, 7

Previous studies estimated brachial artery endothelial and smooth muscle functions by flow-mediated dilatation and glyceryl trinitrate administration at 2-weeks intervals over an 8-weeks cycle and treadmill exercise training in healthy young volunteers; the results demonstrated that 2 weeks of exercise training is sufficient to significantly enhance vascular function.8, 9 Therefore, in young adults, endothelium-dependent vasodilation improves during the early stage of exercise training.10 In addition, brachial artery vascular function, estimated by flow-mediated dilatation/glyceryl trinitrate ratio, improved rapidly in response to 8-weeks combined resistance and aerobic exercise training in both healthy middle-aged adults and type 2 diabetic patients, and this exercise effect was sustained after an 8-weeks intervention.11 These observations suggest that exercise training leads to time-dependent adaptation in brachial artery vascular function, and that this effect may differ according to age and medication states. However, the time course of improvement of age-related central arterial stiffening as a result of exercise training has not been characterized in detail.

Aging leads to the induction of chronic inflammation, which is associated with elevated cardiovascular disease risk.12, 13 Inflammatory biomarkers are associated with arterial stiffness, estimated by pulse wave velocity (PWV), which is correlated with elevated levels of circulating high-sensitivity C-reactive protein, tumour necrosis factor alpha and interleukin-6.14, 15, 16 Moreover, anti-inflammatory treatment significantly reduces arterial stiffness (assessed by PWV) in patients with systemic inflammation.13, 17 In addition, regular exercise induces suppression of inflammatory responses and exerts anti-inflammatory effects.17 Thus, anti-inflammatory effects induced by exercise may improve arterial stiffness in middle-aged and older adults.

Pentraxin 3 (PTX3) acts as an anti-inflammatory protein in atherosclerosis and cardiovascular diseases.18 PTX3 deficiency in mice is associated with development of atherosclerotic lesions and promotion of vascular inflammation,19 whereas PTX3 overexpression in mice leads to suppression of the inflammatory response, indicating that PTX3 has an anti-inflammatory and/or anti-atherosclerotic role.20 Thus, circulating PTX3 levels may be a useful biomarker for cardiovascular events.21 In a recent study, we demonstrated that aerobic exercise training elevated circulating PTX3 levels, concomitant with reduction of arterial stiffness in postmenopausal women.22 Therefore, regular exercise increases PTX3 levels, and this increase may reduce the risk of arterial stiffness risks. However, the time course of elevation of plasma PTX3 level in response to exercise training in middle-aged and older adults remains unclear.

We hypothesised that aerobic exercise training would elevate circulating PTX3 levels in middle-aged and older adults, and that elevated PTX3 may participate in exercise training-induced improvement of central arterial stiffening with advancing age. To test our hypothesis, we assessed the time course of association between training-induced effects on circulating PTX3 level and arterial stiffness at 2-weeks intervals during an 8-weeks exercise intervention in middle-aged and older adults. Increased plasma PTX3 levels at the early stages of exercise training intervention may facilitate a decline in arterial stiffness risk in older adults. On the basis of our findings, we propose that plasma PTX3 levels may be a novel predictive biomarker of exercise training-induced improvement of arterial stiffness in middle-aged and older adults.

Materials and methods

Subjects

Thirty-two older men and women participated in the study (ages: 53–79 years). Subjects were recruited via advertisement from a local community health centre and a community recreation centre. All volunteers provided written informed consent before participating in the study, which was approved by the Ethics Committee of Ritsumeikan University and was conducted in accordance with the Declaration of Helsinki. Subjects were randomly assigned to the exercise (n=16 (5 male, 11 female), 65.0±2.1 year) and the control (n=16 (6 male, 10 female), 67.4±1.5 year) groups. Candidates taking anti-hypertensive, anti-hyperlipidemic or anti-diabetic medications were excluded. Subjects were free of symptoms of diabetes mellitus, hypertension, hyperlipidemia, overt cardiovascular disease and chronic kidney disease, as assessed by medical history and physical examination. None of the participants had a history of smoking. Subjects were sedentary or moderately physically active, and did not participate in any other vigorous sports activity. All of the female subjects were postmenopausal women.

Experimental design

For all subjects, peak oxygen uptake (VO2peak), body weight, height, resting systolic blood pressure, resting diastolic blood pressure, resting heart rate, resting plasma PTX3 concentration and serum concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides were measured at the beginning and end of the 8-weeks intervention. Carotid–femoral PWV (cfPWV) was examined as an index of central arterial stiffness. Furthermore, in the exercise group, cfPWV and plasma PTX3 concentration were measured at 2-weeks intervals for 8 weeks. Before subjects were tested, they sat quietly for 30 min. Resting brachial systolic blood pressure, diastolic blood pressure and heart rate were measured in duplicate in the supine position at rest, using a vascular testing device (OMRON COLIN Co., Tokyo, Japan). Fasting blood samples were drawn following at least 48 h of rest after the last exercise-training session. All subjects were instructed not to eat or drink fluids other than water for at least 12 h prior to blood sampling. Serum and plasma samples were immediately centrifuged (1500 g, 15 min, 4 °C). Blood samples were stored at −80 °C until use. Room temperature was maintained at 24 °C throughout the experiment.

Exercise intervention

Aerobic exercise training programme consisted of cycling on a leg ergometer (828E Monark cycle ergometer, Stockholm, Sweden) for 55 min, 3 days per week, for 8 wk. Each exercise session consisted of a 5-min warm-up period at 40% VO2peak, followed by 45 min of cycling at a resistance that elicited 60–70% VO2peak and ended with a 5-min cool-down period at 40% VO2peak. Exercise compliance was carefully monitored by direct supervision and both heart rate and ratings of perceived exertion (RPE) were recorded during the aerobic exercise. During the aerobic exercise, the average of exercise load was 73.1±1.1 W, the average of heart rate was 115.8±1.3 beats per min, and the average of RPE was 13.1±1.2. In addition, sedentary control subjects were encouraged to maintain their usual activities of daily living during the experiment, and the subjects in both groups were encouraged to maintain their usual food intake during the experiment.

Body composition

Height and weight were both measured with a digital electronic scale (WB-510, TANITA) when the subjects were standing.

Peak oxygen consumption

VO2peak was measured during breath-by-breath assessment using an incremental cycle exercise test on a cycle ergometer (MINATO, AE-310SRD, Osaka, Japan). After the continuous warm-up exercise at mild intensity, which the RPE was 10–12 for 5 min, incremental cycle exercise began at a work rate of 60 W (30–90 W) for men and 30 W (0–60 W) for women, and power output was increased by 15 W min−1 until the subjects could not maintain a fixed pedalling frequency of 60 r.p.m. We monitored heart rate and RPE minute by minute during the exercise. The highest 30-s averaged value of VO2 during the exercise test was designated as VO2peak if three out of four of the following criteria were met: (I) plateau in VO2 with an increase in external work, (II) maximal respiratory exchange ratio1.1, (III) maximal heart rate 90% of the age-predicted maximum (208−0.7 × age) and (IV) RPE18.

Blood pressure

The supine systolic blood pressure, diastolic blood pressure and heart rate were recorded from the left arm using a semi-automated device (form PWV/ABI; OMRON COLIN Co.).

cfPWV

After 15 min of quiet rest in the supine position, subjects were studied in the supine position. cfPWV was measured using applanation tonometry as previously described.23 In brief, cfPWV was measured in triplicate by arterial applanation tonometry, using an array of 15 transducers (form PWV/ABI; OMRON COLIN Co.). The distance travelled by the pulse waves was assessed in triplicate by a random zero-length measurement over the surface of the body using a non-elastic tape measure. Pulse-wave transit time was determined from the time delay between the proximal and distal ‘foot’ waveforms. The foot of the wave was identified as the commencement of the sharp systolic upstroke, which was detected automatically. The cfPWV value was calculated as the distance divided by the transit time. In our laboratory, the coefficient of variation for inter-observer reproducibility of cfPWV was 4.7%.

Plasma PTX3 concentration

Plasma PTX3 concentration was measured as previously described.24 In brief, each blood sample was placed in a chilled tube containing ethylenediaminetetraacetic acid (2 mg ml−1) and centrifuged at 2000 g for 15 min at 4 °C. The plasma was stored at −80 °C prior to analysis. Plasma concentrations of PTX3 were determined using a commercial enzyme-linked immunosorbent assay kit (R&D Systems Inc., Minneapolis, MN, USA).

Blood biochemistry

Serum concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides were determined using standard enzymatic techniques.

Statistical analysis

Data are expressed as means±s.e. The unpaired t-test was used for baseline comparisons between the control and exercise groups. Differences between groups and time points were assessed by using a two-way analysis of covariance model that included age and sex as covariates. A one-way analysis of covariance model that included age and sex as covariates was used to compare differences in the percent change of cfPWV from baseline, which was measured every 2 weeks over 8 weeks in the exercise group. Fisher’s post hoc test was applied in all cases where a measurement was significantly different. Relationships between the percent change in plasma PTX3 levels and cfPWV in the exercise group, measured every 2 weeks for 8 weeks, were determined using the Pearson correlation coefficient. P<0.05 was defined as statistically significant. All statistical analyses were performed using StatView (5.0, SAS Institute, Tokyo, Japan). We calculated the required sample size by using Power and Sample Size Calculations Version 3.0, and then the required sample size to detect the training response of PTX3 concentration and cfPWV in this study was 14 and 14 (α=0.05 and power=0.8).

Results

Table 1 summarizes the characteristics of the subject groups before and after the intervention. There were no significant differences in the baseline value of age, height, body weight, BMI, heart rate, blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride or peak oxygen uptake between the exercise and control groups. The value of VO2peak was significantly higher in the exercise group after the 8-weeks aerobic exercise intervention. There were no significant differences between the two groups in other parameters tested before and after the intervention.

Table 1 Characteristics of the control and training groups

Figure 1 shows the plasma PTX3 concentration and cfPWV before and after the 8-weeks intervention in the control and exercise groups. Before the intervention, there were no differences between the two groups in the baseline plasma PTX3 concentration or cfPWV. There was a significant effect of the interaction between group and time on the plasma PTX3 concentration (P=0.0153). After exercise training, plasma PTX3 concentrations were significantly higher in the exercise group compared with control group (Figure 1a). There was no significant difference in cfPWV between the exercise and control groups before the exercise training, whereas there was significant effect of the interaction between group and time on cfPWV (P=0.0203, Figure 1b). After the exercise-training intervention, cfPWV decreased significantly (Figure 1b). On the other hand, in the control group, there was no significant change in plasma PTX3 concentration and cfPWV between before and after the 8-weeks intervention.

Figure 1
figure1

Plasma pentraxin 3 (PTX3) level (a) and carotid–femoral pulse wave velocity (cfPWV) (b) in middle-aged and older adults before and after 8 weeks of either exercise training (training group, n=18) or sedentary living (control group, n=16). Data are expressed as means±s.e.

Furthermore, changes in plasma PTX3 concentration and cfPWV, measured every 2 weeks for 8 weeks, were observed in the exercise group (Figure 2). Plasma PTX3 concentration was gradually elevated during the exercise intervention, and significantly increased after 4 weeks of the intervention (P<0.05, Figure 2a). On the other hand, cfPWV gradually declined from baseline over the course of 8 weeks, and was significantly reduced after 6 and 8 weeks of the intervention (P<0.05, Figure 2b).

Figure 2
figure2

Time course of change in plasma PTX3 concentration (a) and cfPWV (b), measured at 2-weeks intervals during an 8-weeks exercise intervention in middle-aged and older adults. Data are expressed as mean±s.e.

In addition, we analysed the relationship between the percent change in plasma PTX3 concentration and cfPWV in the exercise group, measured every 2 weeks for 8 weeks. There was no significant relationship between the percent change in plasma PTX3 level and cfPWV after 2 or 4 weeks of the intervention. By contrast, significant negative relationships between the percent change in plasma PTX3 level and cfPWV were observed after 6 weeks (years=−0.04 × −9.53, r=0.54, P<0.05) and 8 weeks (year=−0.04 × +15.18, r=0.51, P<0.05) of the intervention.

Discussion

This study investigated the time course of association between exercise training-induced alterations in circulating PTX3 level and central arterial stiffness in middle-aged and older adults during an 8-weeks aerobic exercise intervention. In middle-aged and older adults, cfPWV gradually declined during the 8-weeks aerobic exercise training, and was significantly reduced after 6 and 8 weeks of the intervention. In addition, plasma PTX3 level was elevated after 4 weeks of the intervention, and this elevation was maintained until the 8 weeks of the exercise intervention. Moreover, the exercise training-induced elevation in plasma PTX3 level was negatively associated with the percent change in cfPWV after 6 and 8 weeks of the intervention; however, this association was not seen at 4 weeks. Therefore, these results suggest that the plasma PTX3 level was elevated earlier in the exercise training intervention than the exercise training-induced reduction of central arterial stiffness; subsequently, the circulating PTX3 was associated with exercise training-induced alternation of central arterial stiffness in the middle and older adults. Thus, plasma PTX3 level may be a predictive biomarker of exercise training-induced improvement of arterial stiffness. Several studies have reported that PTX3 is a novel biomarker of cardiovascular diseases, such as vascular inflammation, atherosclerosis and endothelial dysfunction.18, 25, 26 We propose that circulating PTX3 level might be useful for predicting the training effect of central arterial stiffness.

We observed a negative association between the exercise training-induced alteration of the plasma PTX3 level and central arterial stiffness after 6 and 8 weeks of intervention in middle-aged and older adults. In addition, the exercise training-induced elevation of PTX3 production was already detectable after 4 weeks of the intervention, but no association between changes in PTX3 and cfPWV was apparent at that time. The mechanism underlying the difference between these associations remains unclear. Age-associated chronic inflammation contributes to the development of arterial stiffness.14, 15, 16 This inflammatory response may be related to reduction of nitric oxide (NO) production and/or inactivation of NO via inflammatory cytokines such as C-reactive protein, tumour necrosis factor-α and interleukin-6.12 In a recent study, we demonstrated that aerobic exercise training elevated circulating NO and PTX3 production, concomitant with reduction of arterial stiffness, in middle-aged and older adults.6, 11 Elevated PTX3 production leads to suppression of the inflammatory response, resulting anti-inflammatory and/or anti-atherosclerotic effects.20 In addition, the circulating inflammatory markers are elevated due to the stimulation of acute exercise, leading to increase in arterial stiffness index.27 Therefore, elevation of PTX3 production by exercise training leads vascular anti-inflammatory responses and promotes NO production; thereafter, time until these responses reduce the risk of arterial stiffness may be needed. Although these results may suggest a cause-and-effect relationship between PTX3 and central arterial stiffness, further study is necessary to characterize the time course of changes in NO production and the anti-inflammatory response in the artery.

In the middle-aged and older adults who participated in this study, central arterial stiffness gradually declined from baseline over the course of 8 weeks, and was significantly reduced after 6 and 8 weeks of the intervention. In two previous studies, a 2-weeks cycle and treadmill exercise training elevated brachial artery endothelial and smooth muscle functions, as estimated by flow-mediated dilatation and glyceryl trinitrate administration, in healthy young volunteers, whereas this training effect returned to baseline levels after 6–8 weeks of exercise training.8, 9 In addition, brachial artery vascular function, assessed using the flow-mediated dilatation/glyceryl trinitrate ratio, in both healthy middle-aged adults and type 2 diabetic patients was improved by 2-weeks combined resistance and aerobic exercise training; subsequently, this improvement was sustained throughout the 8-weeks intervention.11 These observations suggest that the time course of exercise training-induced improvement in central arterial stiffness in middle-aged and older adults differs from that of brachial artery vascular function in healthy young and middle-aged subjects and type 2 diabetic patients.

In a recent study, we demonstrated that 8-weeks aerobic exercise training significantly increased the circulating PTX3 level in middle-aged and elderly women.22 Moreover, endurance-trained men have higher plasma PTX3 concentrations than sedentary men.24 In addition, a single bout of exercise at 60–75% maximal oxygen uptake elevates circulating PTX3 level in healthy male and female subjects.28, 29 In this study, circulating PTX3 level was elevated after 4 weeks of exercise training intervention in middle-aged and older adults. Slusher et al.29 demonstrated that plasma PTX3 level was elevated after a single bout of continuous aerobic exercise. Acute aerobic exercise increases lumen blood flow, and consequently induces pulsatile shear stress in arterial endothelial cell. Lumen shear stress in human aortic endothelial cell elevates nuclear factor κB and activator protein-1 activations,30, 31 and this transcriptional factor activation leads to the expression of PTX3 gene.32, 33 Thus, chronic repetition of endothelial cell stimulation mediated by exercise-induced shear stress may be necessary to achieve basal high plasma PTX3 level via aerobic exercise training.

In this study, the origin of plasma PTX3 remains unclear, because the PTX3 protein is expressed in multiple tissues, including endothelial cells, fibroblasts, hepatocytes, monocytes, heart, muscle, ovary, kidney, lung and so forth. Therefore, future studies should examine the change in PTX3 gene expression in each tissue in response to exercise training. In addition, we observed the association between the training-induced change in plasma PTX3 level and arterial stiffness in middle-aged and older adults. Therefore, PTX3 may reduce arterial stiffness by reducing inflammation. However, we did not investigate the advantageous effects of exercise training on inflammatory cytokines, such as high-sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor alpha in this study. Moreover, older individuals possessing more body fat tend to experience increased arterial stiffness,32 however, this study did not measure body fat. Therefore, further study is needed to examine circulating inflammatory cytokines in response to exercise training, as well as the relationship between circulating PTX3 and arterial stiffness after adjustment for body fat. Finally, this study was an intervention study with a small sample size of healthy subjects; therefore, future studies should examine these effects in a large sample size in the elderly.

In conclusion, we found that in middle-aged and older adults, cfPWV declined after 6 weeks, and plasma PTX3 level was elevated from 4 weeks until the end of the 8-weeks aerobic exercise intervention. In addition, the exercise training-induced elevation of the plasma PTX3 level was negatively associated with the change in cfPWV after 6 and 8 weeks of the intervention, but this association was not apparent after 4 weeks. These results suggest that the plasma PTX3 level was elevated at the early stage of exercise training intervention, and was subsequently associated with exercise training-induced alteration of central arterial stiffness in the middle and older adults. Thus, circulating PTX3 could be used as an efficient predictor of exercise training-induced improvement of arterial stiffness.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI: #26282199 and # 25560378 for M Iemitsu).

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Zempo-Miyaki, A., Fujie, S., Sato, K. et al. Elevated pentraxin 3 level at the early stage of exercise training is associated with reduction of arterial stiffness in middle-aged and older adults. J Hum Hypertens 30, 521–526 (2016). https://doi.org/10.1038/jhh.2015.105

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