|Year : 2020 | Volume
| Issue : 1 | Page : 10-15
Effect of an 8-week endurance rehabilitation exercise on apoptosis in cardiac patients
Maryam Dadaei1, Parvaneh Nazarali1, Rostam Alizadeh2
1 Department of Exercise Physiology, Faculty of Sports Science, Alzahra University, Tehran, Iran
2 Department of Sports Science, School of Literature and Humanities, Ilam University, Ilam, Iran
|Date of Submission||29-Nov-2019|
|Date of Decision||11-Jan-2020|
|Date of Acceptance||12-Feb-2020|
|Date of Web Publication||24-Apr-2020|
Dr. Parvaneh Nazarali
Department of Exercise physiology, Faculty of Sports Science, Alzahra University, Tehran
Source of Support: None, Conflict of Interest: None
Aims: Exercise training is one of the nonpharmacological treatments for heart diseases. The aim of this study was to investigate the effect of 8-week endurance rehabilitation training on apoptosis among cardiac patients. Subjects and Methods: Sixteen postcoronary artery bypass grafting patients, having examined by specialists, were randomly assigned to control (n = 8) and experimental groups (n = 8). The experimental group completed a training protocol including running on a treadmill at 55%–70% of their maximum heart rate for 8 weeks. Blood sampling was performed after 12–14 h of fasting and before and after the 8-weeks training to measure biochemical variables. The measurement of Bax and B-cell lymphoma-2 (Bcl-2) was conducted using the ELISA kit. The data analysis was carried out using the independent sample t-test at P ≤ 0.05. Results: The results showed a significant difference between the participants' mean Bax (P = 0.011) and Bcl-2 (P = 0.015) values after the intervention for both the groups. Likewise, the difference between the ratios of Bcl-2/Bax values after the intervention was significant for both the groups (P = 0.023). Conclusions: According to the findings of the study, it seems that the endurance rehabilitation training exercises could have a protective effect against apoptosis.
Keywords: Apoptosis, cardiac patients, rehabilitation exercises
|How to cite this article:|
Dadaei M, Nazarali P, Alizadeh R. Effect of an 8-week endurance rehabilitation exercise on apoptosis in cardiac patients. Res Cardiovasc Med 2020;9:10-5
|How to cite this URL:|
Dadaei M, Nazarali P, Alizadeh R. Effect of an 8-week endurance rehabilitation exercise on apoptosis in cardiac patients. Res Cardiovasc Med [serial online] 2020 [cited 2020 Jun 5];9:10-5. Available from: http://www.rcvmonline.com/text.asp?2020/9/1/10/282431
| Introduction|| |
Apoptosis generally affects myocardial cardiomyocytes from both external and internal pathways. On the outer path, death messages such as tumor necrosis factor-alpha (TNF-α) activate the cell membrane death receptors, activate the caspases, and thus trigger the process of apoptosis. In the internal path, the endoplasmic and mitochondrial networks play a major role. In this pathway, mitochondrial centrality is important in the creation of apoptosis.
Increasing the oxidative stress caused increased mitochondrial membrane permeability. As permeability of the membrane increases, cytochrome C, existing in the mitochondrial membrane and membranous space, is released into the cytosol and connects to an apoptosis protease-activating factor and forms a compound called deoxyadenosine triphosphate (dATP); this compound ultimately induces cell apoptosis. This process is carried out by some mitochondrial proteins including the proteins of B-cell lymphoma-2 (Bcl-2) family, which are divided into two main antiapoptotic proteins (Bcl-2, Bcl-XL, Bcl-W, and Bfl-1) and preapoptotic proteins (Bcl-Xs, Bid, Bax, Bak, Bad, Bik, and Bim)., It has been substantiated that genes of the Bcl-2 family contribute to the cell death process. Among the proteins of Bcl-2 family, Bax and Bcl-2 have shown to play an important role in accelerating the onset or inhibition of apoptosis, respectively. In response to the oxidative stress in the mitochondria, the outer membrane of the mitochondria becomes permeable, causing the Bax to transfer from the cytosol to the mitochondria. In general, this gene is limited to mitochondrial membrane space. The transfer of this preapoptotic protein is controlled by the family of Bcl-2 proteins. Therefore, the key element of apoptosis, which is expressed and regulated in the heart, is the Bax and Bcl-2 genes.
Today, it is widely accepted that physical activity induces major homeostatic changes in the internal environment of the body which means challenging cells to survive under stress conditions. Regular physical activity has always been used to rehabilitate cardiac function among cardiovascular patients. Nevertheless, uncertainty still exists regarding the response of apoptotic agents Bax and Bcl-2 and more importantly their ratio (Bax/Bcl-2) to exercise training programs in cardiac patients. Therefore, this study investigated the effect of endurance rehabilitation exercises on Bax, Bcl-2, and Bax/Bcl-2 in cardiovascular patients.
| Subjects and Methods|| |
The participants of the study were 16 postcoronary artery bypass grafting men with the general characteristics [Table 1], who were referred to the Sadr Cardiovascular Rehabilitation Center by the specialist physician. First, the participants completed a demographic questionnaire; then, they were provided written informed consent for their voluntary participation in the study; this was approved by the Ethics Committee of Sport Sciences Research Institute of Iran (SSRI): IR. SSRI. REC.1397.436. All the patients were able to walk on the treadmill; they were also matched in terms of the MET and were randomly divided into two groups. The participants' practical capacity and maximum heart rate were obtained based on the modified Bruce protocol at the beginning and end of the 8-week rehabilitation period. During the rehabilitation program, the patients continued to take the medications prescribed by the specialist physician and maintained regular contact with their physician (all the patients had the same therapeutic program). During the exercises, the participants were fully cared for, and the patients of both the groups were asked to have no changes in their diet or drug regimens. The number of samples in the current study was calculated based on the weighted variance in previous studies and the Cochran formula .
Criteria for inclusion in the study
(1) The individuals who were referred to the cardiovascular rehabilitation unit with the age range of 55–70 years, (2) the patients who were not professional athletes, had not taken any regular exercise program during the past 6 months, and had not participated in any other sports during any research program, (3) the individuals who had undergone cardiac bypass surgery, and at least 3 months had passed since the surgery, (4) the patients who were nonsmokers, (5) those who did not have any changes in their diet during the study, and (6) those who had not taken any supplements in the past 6 months were included in the study.
Criteria for exclusion from the study
(1) The individuals who experienced any restrictive conditions for exercising (nervous, muscular, and skeletal problems) during the study, (2) the patients who did not attend more than three consecutive sessions or a total of four sessions in the exercise program, (3) the patients with high blood pressure, unstable angina, and ventricular arrhythmia, (4) the patients with the aortic valve disease in addition to the coronary artery disease, (5) the patients with gastric ulcer and stomach upsets, (6) the patients with any heart problems inhibiting physical activities, (7) those with any changes in the dosage, type, or discontinuation of the drugs used in the study samples during 8 weeks, and (8) the patients taking neurological or sedative medications were excluded from the study.
Experimental design overview
In the first session (the familiarization session), patients were acquainted with the experimental procedure. On the second visit, practical capacity and maximum heart rate of the patients were obtained based on the modified Bruce protocol. Blood sampling was performed on the third session to measure Bax and Bcl-2, and after that, the patients took part in an 8-week exercise training program. During the rehabilitation program, patients continued to use medications prescribed by the specialist physician and maintained the regular contact with their physician (patients had the same therapeutic program). During the exercises, the patients were fully cared for, and the patients of both the groups were asked to have no changes in their diet or drug regimens. Then, the changes in their electrocardiography and heart rate were recorded and controlled. Forty-eight hour after the last training session blood sampling was repeated to measure the levels of Bax and Bcl-2.
Modified Bruce protocol
The protocol was conducted by a trained nurse, the researcher, and cardiologist at the rehabilation center to estimate the practical capacity and maximum heart rate at the beginning and the end of 8 weeks of training. Before conducting the test, the patients were given the necessary hints. The exercise test was continued before symptoms of severe heart angina, ataxia, dizziness, cyanosis, severe pale coloration, or electrocardiographic changes including dangerous arrhythmias, ST-segment drops more than 1 mm in non-Q diagnostic lids. Since direct measurement of peak oxygen consumption is difficult, the indirect method was used to determine it as follows. First, using the standard modified Bruce exercise test and the 12-lead electrocardiogram device, the duration of the exercise test and the maximum duration obtained at the last minute of the patient attempt were determined. In addition, based on the principle that maximum MET is directly related to maximum oxygen consumption during exercise and each metabolic equivalent (MET) is equal to 3.5 ml O2/kg/min. The amount of oxygen consumed by each patient, according to the duration of the activity, was measured using the following formula:
VO2 max (ml/kg/min) = 14.76− (1.379 × T) + (0.451 × T2) − (0.012 × T3)
Exercise training protocol
The experimental group performed the rehabilitation program three sessions per week for 8 weeks. Each rehabilitation session lasted 45–60 min, including 15 min of warm-up (strength exercises with simple rhythmic movements), 25–30 min of running on the treadmill at an intensity of 55%–70% of maximum heart rate, and 10–15 min of cooldown. Heart rate and electrocardiographic changes were controlled during exercise. Adherence to the principle of overload for each patient was defined according to his specific conditions. During the practice, the Borg scale was used to allow each patient to declare self-concept of the effort. The ambient temperature was controlled around 26°C–30°C.
Sampling and blood analysis
After 12 h of fasting at night, the patients attended the laboratory at 8 am. Then, the initial blood sample was taken at 5 cc by the blood sampling specialist of the laboratory from the anterior muscular vein to determine the levels of the desired factors. After that, the blood sample was centrifuged and its serum samples were separated and frozen at −70°C. The initial data were collected and the training program began the next day and continued for 8 weeks. Forty-eight hour after the last training session, anthropometric and laboratory measurements were performed again at the same time and condition as the initial tests with the same instruments by the researcher and laboratory specialist. The measurement of BCI2 and BAX was conducted by the ELISA method using the EASTBIOPHOPHARM Company's human kit.
All values in figures are presented as the mean ± standard deviation (M ± SD). The statistical package for social sciences version 22 (IBM, Armonk, NY, USA) was used for statistical analysis. Shapiro–Wilk normality test was conducted on each set of dependent variables. The independent t-test was used to statistically analyze the research data. In addition, since the Bcl2 and Bax units were different, the percentage of their pretest and posttest changes was calculated and then their ratio was obtained. In case of a significant difference between the groups, since the number of patients in the groups is identical, Bonferroni post hoc test was used. Statistical significance was accepted at P < 0.05.
| Results|| |
The general characteristics of patients are reported in [Table 1], the mean SD and percent change of the factors considered are presented in [Table 2], and the independent t-test results are presented in [Table 3].
At the beginning of the study, no significant difference between the pretest of the measured factors Bcl2 (P = 0. 15), Bax (P = 0. 78), and MET (P = 0. 78) was detected.
There was a significant difference between patients' weight changes (P = 0.037) and MET (P = 0.015) between the two groups; however, the difference was not significant between BMI (P = 0.155) and EF (P = 0.46).
[Table 3] shows the results of the independent t-test for BCL-2 [see [Figure 1] Bax, [see [Figure 2] factors, and Bax/Bcl2 ratio in the two groups, suggesting a significant difference between the two groups.
|Figure 1: B-cell lymphoma-2 levels at pre and post (after 8 weeks of intervention) in experimental group and control group. Significant differences are marked by “*”|
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|Figure 2: Bax levels at pre and post (after 8 weeks of intervention) in experimental group and control group. Significant differences are marked by “*”|
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| Discussion|| |
The results of the present study showed that 8-weeks endurance rehabilitation exercise significantly increased BCL-2 levels of patients in the experimental group. In this regard, Siu et al. showed that 8-week moderate-intensity aerobic exercise increases Bcl-2 levels in the myocardium. Exercise may help to reduce the risk of apoptosis in the present study by reducing the TNF-α factor and associated signaling. However, in the present study, the levels of the TNFα were not measured, which is one of the limitations of the study.
Although the precise mechanism of apoptosis is still unclear, it may differ depending on the cell type and type of stimuli. It has been shown that exercise induces apoptosis, which is a natural process for destroying damaged cells in which significant inflammatory reactions do not occur. This process ensures the normal functioning of the body. Protective mechanisms against apoptosis due to prevention may be affected by nuclear factor kappa B, which prevents sensitivity to apoptosis and can enhance regulation of increase in the antiapoptotic Bcl-2 cells. Furthermore, Kang et al. found that apoptosis in myocytes predominates after reoxygenation through mitochondrial apoptotic pathway; in addition, Bcl-2 prevents apoptosis from oxygenation by inhibiting cytochrome C release from the mitochondria. Oxidative stress is an important initiator of apoptosis in the heart cells, especially after revascularization in ischemic tissues. The basic levels of oxidative stress also increase with age and may help to increase the signaling of apoptosis in the myocardium of healthy animals. It has been shown that exercise is effective in reducing apoptosis and apoptotic signaling in response to acute myocardial disorders. As mentioned, the mechanism of exercise in coping with myocardial apoptosis is not fully understood. However, a study by French et al. suggests that at least in some parts, improvement in the function of antioxidant enzymes in the myocardium, including MnSOD activity, may contribute to modifying apoptosis. This is an important point of view that highlights the importance of therapeutic exercise for improving antioxidant signaling as a means of preventing apoptosis in response to ischemia acute myocardial revascularization. It also seems that exercise lowers apoptosis signaling in nonischemic and aging conditions, while oxidative stress is expected to be much lower than that of ischemic revascularization.
However, the results of this study are not consistent with the findings of Sun et al. and Santana et al.,, Sun et al. indicated that a session of exhaustive swimming activity would significantly reduce the expression of the Bcl-2 gene within 6 h after exercise. Santana et al. found that 13-week endurance activity increased the expression of the “promoter of death” (Bad) gene in the myocardium tissue but did not affect the protein content of this proapoptotic index. The amount of Bcl-2 gene expression and protein content decreased significantly after the training period. Contradiction in results may be related to factors such as the low duration of exercise in each session or training period or abnormal levels of apoptosis-regulating factors in patients. In addition, this contradiction with the above researchers can be justified according to the type of patient and the type of practice protocol. In most of the above studies, animal samples have been used and resistance protocols have been used in the research design.
Furthermore, the findings of the present study indicate that 8-week endurance rehabilitation exercises significantly reduced Bax levels in the experimental group. In this regard, Lu et al. reported that both exercise methods (interval and continuous) reduced the expression of BAX and caspase-3 gene expression with the same size and significantly increased myocardial Bcl-2 in comparison with the control group. Although the mechanism of the Bax process is not obvious, Bcl-2 prevents the increase of Bax. In this study, we also observed an increase in Bcl-2 in the training group, so it seems that Bcl-2 is one of the Bax suppression mechanisms. Increasing Bcl-2 by consolidating the mitochondrial wall, suppressing Bax, preventing the release of cytochrome c, regulating the release of calcium from sarcoplasmic, and reducing the effect of ROS from exercise increase cellular immunity and prevent stress-induced apoptosis.
For example, Olivetti et al. showed that myocytic apoptosis significantly increases in the heart of patients with heart failure. Saraste et al. also showed that the number of myocytes exposed to apoptosis increased significantly in human heart failure in comparison to myocardial infarction among the control group, and the expression of Bcl-2 increased in heart failure. Increasing the expression of Bcl-2 in the heart of patients after coronary artery bypass surgery showed that compensatory mechanisms have been activated to prevent apoptosis through endurance exercises.
However, the results of this study are not consistent with the findings of Lajoie et al. (2004), and Li et al. (2016)., Lajoie et al. (2004) evaluated the effect of moderate-intensity aerobic exercises on apoptotic and anti-apoptotic factors in the heart tissue of hypertensive rats. The results showed that aerobic exercises increased the myocardium HSP-72, BAX, and Bcl-2, but the Bcl-2/BAX ratio did not change. Li et al. (2016) showed that doing exercise immediately after a stroke resulted in a significant increase in apoptosis in brain of rats with cerebral ischemia through increasing BAX and decreasing Bcl-2. As can be seen, very few studies have been conducted on the effect of exercise on BAX, which according to differences in measurements from different tissues and differences in the type and intensity of activity, different subjects, and time of measurement, inconsistent results have been reported.
Moreover, the results of this study indicated that there is a significant difference between the Bax/Bcl2 ratios of patients in the two groups after 8-weeks endurance rehabilitation exercises. In this regard, Delchev et al. (2006) reported that exercise increased the Bcl2-to-BAX ratio.
It has been shown that Bax/Bcl-2 ratio is significantly regulated positively in the left ventricle after exercise. In fact, the balance between Bax/Bcl-2 is considered as an important factor in determining the increase in apoptosis in cardiac myocytes.
Apoptosis regulatory protein cells are modestly balanced, and there is a complex balance among factors causing apoptosis and the factors that counteract apoptosis. The Bax/Bcl2 ratio has the closest relationship to determining the survival or death of apoptotic cells. In this study, the Bax/Bcl2 ratio of patients in the two groups was significantly different in the post-intervention period. This result suggests that exercise may have increased the Bax/Bcl2 ratio in favor of cellular life through modulation of the induction of internal apoptosis of Bax and p53 and the prevention of cytochrome c release as well as the suppression of external factors such as TNF-α and ROS and can have a protective effect in emergence of apoptosis. However, the results of this study are not consistent with the findings of Lajoie et al. and Colombo et al. (2015). Lajoie et al. evaluated the effect of moderate-intensity aerobic exercises on apoptotic and antiapoptotic factors in the heart tissue of rats suffering from hypertension. The results showed that aerobic exercises increased the myocardium HSP-72, BAX, and Bcl-2; however, the Bcl-2/BAX ratio did not change. On the other hand, Colombo et al. showed that 5-week aerobic exercise with a 60% maximal oxygen content used caused an insignificant increase in caspase-3 and pAkt-2 and an insignificant decrease in Bax/Bcl-2.
As noted above, different results have been obtained in some cases in studies conducted in this field, and the reports presented are ambiguous. The contradiction in the reported researches can be attributed to factors such as type, intensity, and duration of the training period. The inconsistency in the results may be due to different methods used. Even in some cases, the different conditions of patients may affect the heterogeneous results in terms of age, sex, and physical fitness, which require more studies with all aspects and simultaneous measurement of apoptotic variables.
| Conclusions|| |
In summary, the results of this study indicated that 8-week endurance rehabilitation exercises significantly increased the BCL-2 levels and decreased the Bax levels. Moreover, there was a significant difference between the Bax/Bcl2 ratios after the intervention for the two groups. Given that in the present study, (1) human participants and the aerobic training intervention (for the experimental group) were employed, (2) the study involved a control group, (3) the participants' assignment to the groups was random, (4) the statistical analyst was not fully aware of the nature of the research work, and (5) the research samples did not differ significantly in terms of the measured factors at the beginning of the study. It seems that endurance rehabilitation exercises could have a protective effect against apoptosis. However, given the few studies conducted in this context, the relationship between exercise, apoptosis, and heart disease needs to be further elucidated.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Sadowski-Debbing K, Coy JF, Mier W, Hug H, Los M. Caspases-their role in apoptosis and other physiological processes as revealed by knock-out studies. Arch Immunol Ther Exp (Warsz) 2002;50:19-34.
Wang ZB, Liu YQ, Cui YF. Pathways to caspase activation. Cell Biol Int 2005;29:489-96.
Delchev SD, Georgieva KN, Koeva YA, Atanassova PK. Bcl-2/Bax ratio, mitochondrial membranes and aerobic enzyme activity in cardiomyocytes of rats after submaximal training. Folia Med (Plovdiv) 2006;48:50-6.
Lu K, Wang L, Wang C, Yang Y, Hu D, Ding R. Effects of high-intensity interval versus continuous moderate-intensity aerobic exercise on apoptosis, oxidative stress and metabolism of the infarcted myocardium in a rat model. Mol Med Rep 2015;12:2374-82.
Marzetti E, Privitera G, Simili V, Wohlgemuth SE, Aulisa L, Pahor M, et al
. Multiple pathways to the same end: Mechanisms of myonuclear apoptosis in sarcopenia of aging. ScientificWorldJournal 2010;10:340-9.
Kirshenbaum LA, de Moissac D. The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 1997;96:1580-5.
Maulik N, Sasaki H, Addya S, Das DK. Regulation of cardiomyocyte apoptosis by redox-sensitive transcription factors. FEBS Lett 2000;485:7-12.
Alipour M. Cardiac Electrophysiology and Pacemaker Therapy Exercise and Cardiopulmonary Effects. Tehran: Hayyan Publication; 2007. p. 73-7.
Siu PM, Bryner RW, Martyn JK, Alway SE. Apoptotic adaptations from exercise training in skeletal and cardiac muscles. FASEB J 2004;18:1150-2.
Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C. Doxorubicin treatmentin vivo
causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 2002;62:4592-8.
Mooren FC, Blöming D, Lechtermann A, Lerch MM, Völker K. Lymphocyte apoptosis after exhaustive and moderate exercise. J Appl Physiol (1985) 2002;93:147-53.
Kang PM, Haunstetter A, Aoki H, Usheva A, Izumo S. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ Res 2000;87:118-25.
Marín-García J, Goldenthal MJ. Mitochondrial centrality in heart failure. Heart Fail Rev 2008;13:137-50.
Kavazis AN, McClung JM, Hood DA, Powers SK. Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli. Am J Physiol Heart Circ Physiol 2008;294:H928-35.
French JP, Hamilton KL, Quindry JC, Lee Y, Upchurch PA, Powers SK. Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. FASEB J 2008;22:2862-71.
Kwak HB, Song W, Lawler JM. Exercise training attenuates age-induced elevation in Bax/Bcl-2 ratio, apoptosis, and remodeling in the rat heart. FASEB J 2006;20:791-3.
Sun Y, Cui D, Zhang Z, Zhang T, Shi J, Jin H, et al
. Attenuated oxidative stress following acute exhaustive swimming exercise was accompanied with modified gene expression profiles of apoptosis in the skeletal muscle of mice. Oxid Med Cell Longev 2016;2016;1-8.
Mejías-Peña Y, Estébanez B, Rodriguez-Miguelez P, Fernandez-Gonzalo R, Almar M, de Paz JA, et al
. Impact of resistance training on the autophagy-inflammation-apoptosis crosstalk in elderly subjects. Aging (Albany NY) 2017;9:408-18.
Santana ET, Serra AJ, Silva Junior JA, Bocalini DS, Barauna VG, Krieger JE, et al
. Aerobic exercise training induces an anti-apoptotic milieu in myocardial tissue. Motriz: Rev Educ Física 2014;20:233-8.
Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout GB, Bahar I. Bistability in apoptosis: Roles of bax, bcl-2, and mitochondrial permeability transition pores. Biophys J 2006;90:1546-59.
Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, et al
. Apoptosis in the failing human heart. N
Engl J Med 1997;336:1131-41.
Saraste A, Pulkki K, Kallajoki M, Heikkilä P, Laine P, Mattila S, et al
. Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur J Clin Invest 1999;29:380-6.
Lajoie C, Calderone A, Béliveau L. Exercise training enhanced the expression of myocardial proteins related to cell protection in spontaneously hypertensive rats. Pflugers Arch 2004;449:26-32.
Li F, Shi W, Zhao EY, Geng X, Li X, Peng C, et al
. Enhanced apoptosis from early physical exercise rehabilitation following ischemic stroke. J Neurosci Res 2017;95:1017-24.
Condorelli G, Morisco C, Stassi G, Notte A, Farina F, Sgaramella G, et al
. Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation 1999;99:3071-8.
Greijer AE, van der Wall E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 2004;57:1009-14.
Krüger K, Mooren FC. Exercise-induced leukocyte apoptosis. Exerc Immunol Rev 2014;20:117-34.
Zhu S, Li M, Figueroa BE, Liu A, Stavrovskaya IG, Pasinelli P, et al
. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci 2004;24:5909-12.
Colombo R, Siqueira R, Conzatti A, Fernandes TR, Tavares AM, Araújo AS, et al
. Aerobic exercise promotes a decrease in right ventricle apoptotic proteins in experimental cor pulmonale. J Cardiovasc Pharmacol 2015;66:246-53.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]