The results of present study showed significant increase in endurance capacity, duration and running distance of male Wistar rats that following two-weeks high intensity interval training, which indicated the physiological effects of selected exercises training on performance and physiological adaptations of rat [52].
The results showed that levels of c-kit receptor protein tissue were statistically significant increase in training (T), MI and T + MI groups compared with the control group. Studies have shown that stem cell factor (SCF) and its receptor C-kit play an important role in the migration of endogenous stem cells to infarct areas after MI. kuang et al (2008) showed that the expression of SCF / C-kit significantly increased immediately after MI in the rats. They concluded that the over expression of SCF and its receptor in the infarcted area was associated with the accumulation of stem cells [53]. And they also claimed that the presence and expression of SCF, which is a factor in the accumulation of stem cells, depends on the content of expression of the receptor of the C-kit. On the other hand, Chuan Hang et al (2011) in a study showed that the adult heart has a small number of cells expressing stem cell markers such as C-kit, SCa-1 and MDR-1 [54].
The results of this study showed that the expression of C-kit receptor expression after two weeks high intensity interval training with acute myocardial infarction was significantly increased compared to control group. Studies has shown that following exercises training, the stem cells recruitment of C-kit and also the expression of NKX2 /5 and GATA4 (the key factors transcription of the cardiac stem cells) is increased [55, 56]. In addition, exercise training activates the PI3K / AKT signal pathways in the myocardial infarcted area and beneficial effects are induced through recruitment of C-kit + cells by increasing the synthesis of DNA in the heart infarcted area (57). In this relation, Ellison and et al also showed that the exercise training increases the ratio of cardiac to body weight, volume of myocytes and salso the number of cardiac stem cells in the training group by 5 folds in the ventricular wall. They were also showed that exercise training Exercise in the first, second, and third weeks resulted in C-kit expression in the left ventricle of rat, but this increase was observed in the right ventricle in the third week [58]. Exercise training with controlled intensity increases the expression of growth factors, initiates the regeneration of myocytes, and then activates the differentiation of the C-Kit, which results in the production of new heart cells. This finding suggests that cardiac physiological adaptation depends on the intensity and duration of the exercise [58].
The results of this study showed that SDF-1a and its receptor CXCR4 concentration in three groups significantly increased with control group and also, the tissue concentration of these proteins in the T + MI group was significantly higher than that of the training group. The findings have shown that, during the ischemia and hypoxia, key family factors (HIFs) that directly activate and increase the growth factors (SCF, HGF, VEGF, PDGF), chemokines (SDF-1a) and cytokines [59, 60, 61]. The expression of SDF-1a is regulated through the HIF pathway in endothelial cells and its expression in ischemic tissue is proportional to the amount of oxygen depletion [59, 62]. Accordingly, the SDF / CXCR4 axis is associated with cardiac survival, new angiogenesis, and cardiac cardiac function after cardiac infarction [63]. Recent studies have shown that the SDF/CXCR4 signal axis plays role in reducing infarcted size and improving left ventricular function in ischemic injury-redundant models [64]. On the other hand, following the ischemia in tissue with the activation of the SDF-1a / CXCR4 signal axis, the migration of CPC / C-kit + stem cells to infarction area increases [65, 66]. In this relation, Tang et al found that hypoxia increased the expression of CXCR4 and HIF-1a increased CLK / C-kit + migration through SDF-1a [20]. It is necessary to express that CPC / C-kit + cells are endogenous stem cells in the adult heart that are responsible for the regeneration of cardiac myocyte in physiologic and pathological conditions [20]. Studies have shown that stem cell migration is enhanced by the pathways of SDF-1a / CXCR4 and SCF / C-kit, which plays its role by blocking the pathway of signal p38-MAPK (a factor in reducing the migration of stem cells) [54]. The research that done by Ding (2013), showed that crosstalk between the SDF-1α / CXCR4 and SCF / C-kit signaling pathways plays an important role in profibrotic by recruitment endogenous C-kit stem cells [32]. The researches also showed that the expression of the receptor of the C-kit induces MMP-9 activity, which is necessary for the proliferation and migration of the progressive C-kit stem cells to the cardiac after the MI [31]. On the other hand, TNF-α binding to the C-kit receptor is overexpressed by the C-kit receptor, which increases the regeneration of injuries cardiac cells [31].
Also, other signaling pathways are activated by axis SDF-1a / CXCR4, which results in cell survival and stem cell proliferation. So that, the expression of CXCR4 is PI3K / AKT phosphorylation mediator, which that results in upregulate vascular growth factor (VEGF) regulation [33]. AKT and ERK1 / 2 are another signal path that is activated by the SDF-1a/CXCR4 axis, which inactivates the BAD protein expression (associated with cell death) [34, 35]. It also increases the expression of cell protect and survival proteins such as BCL2, BCL-XL, Notch-1, β-catenin and NK-KB. The CAMP / PKA signal path is another path that is activated by the SDF-1a/CXCR4 axis, which is necessity for the migration of stem cells to injuries areas [67].
Research showed that tissue ischemia increased the expression of SDF-1, which activates the STST3 signal pathway, and improves cell growth and inhibits cell apoptosis [54]. STAT3 is a protective pathway in the heart that, by activating several downstream signal pathways, expresses BCL2, BCL-XL, HSP, and angiogenic factors and decreases the secretion of inflammatory cytokines [68].
Pathologic results the present study showed that subcutaneous injection of isopretonol in two continues days caused severe pathological changes such as edema, neutrophilic accumulation, tissue disruption and hemorrhage in rat’s cardiac tissue. It also significantly increases indexes injuries cardiac such as LDH, CK total, CKMB enzymes and troponin T enzyme compared to the control and training groups, which was consistent with the results of the study by Farvin et al (2010) and tofighi et al (2016) [69, 70]. On the other hand, the results of this study showed that cardiac injury factors in T + MI group were less than that in the MI group, which may be the result of the protective effect of exercise training against ischemic attacks and cardiac infarction. The results of this study were similar to the results of Lebo et al (2011) and Nuno et al (2012) [71, 72]. Several studies have reported that exercise training protects against cardiac MI in animal models Induces [73, 74, 75, 76, 77]. It seems to Regular training periods one of the best and most effective and tolerant approaches that cause cardiac protection [37]. Anatomical and physiological changes in the coronary arteries, head shock protein (HSPS), increased activity of cyclooxygenase-2 (COX-2), increased endoplasmic endothelial stress (ER), enhanced potassium function of ATP-dependent sarcolemma (sarcoKATP), increased levels of ATP-dependent potassium channels in mitochondria (mitoKATP), nitric oxide (NO), and increased the antioxidant capacity of the myocardium are among the cellular-molecular mechanisms involved in cardiac protection from cardiovascular injuries [76, 78]. In this field, this study showed that the increase in the chemokine SDF and its receptor, as well as the C-kit receptor, would result in cardiac protection and regeneration by high intensity interval training. In the present study and other studies, it has been shown that under normal conditions, the levels of SDF-1α and its receptor CXCR4 in the heart tissue is insignificant [9, 39], but in different physiological conditions such as intense training, hypoxia and ischemia, as well as pathological conditions (Such as acute myocardial infarction), the concentration of these factors changes [79, 80]. In a similar study, researchers showed that serum levels of chemokines such as SDF-1α and stem cells, increased after one-session endurance training, and they increased this as a result of increased levels of cytokines in the trained peoples [11, 81]. These results were similar to the results of the present study, which showed that the high intensity interval training of SDF-1α tissue concentration increased. It seems that exercise training through induce ischemia and low hypoxia in various tissues of the body, including the cardiac, increases the level of SDF-1α and other stem cell promoters, and this increase can recruitment the stem cell to the ischemic and hypoxia tissue [40]. In this field, various conclusions have been reported from the effect of exercise training on the levels and effects of chemokines by researchers, as Sen et al (2015) and Sarto et al (2007) showed that following the performance of various exercises training, the levels of SDF-1a increased significant [40, 79]. They report that the probable reasons for the significant increase in the SDF-1a / CXCR4 axis were in cardiac increased cortisol levels due to exercise stress, which plays a key role in the onset of the AKT / PKB signal cascade, which improves cardiac function, improves ejection fraction, left ventricular fractional shortening, increased left ventricular wall thickness and recruitment of stem cells [41, 81]. Another study by Mendes-Fereer et al (2008) found that acute activity exercise and long-term exercise training led to the release of catecholamine’s that increase the movement of the progressive hematopoietic stem cells and also the acute and exercise training of the receptor expression Beta-adrenergic α1,2 and β2 increased, via increasing the expression of MMP-9, which is essential for the migration of progressive hematopoietic stem cells [82], In addition, the release epinephrine by the exercise activity of induced expression the receptor of GSK3β, which cause increases the sensitivity of the chemotactic signaling pathways of SDF-1 and this of via induce remodeling of cytoskeletons [83].
Although there is a need for confirmation based on future studies, it can be reasoned that this is probably due to the fact that the tissue levels of SDF, CXCR4, and C-KIT in the training group and training- myocardial infraction group compared to the myocardial infraction group, despite of increasing the values was not statistically significant. The results of this study in tissue injuries showed that exercise training have a pathway of cardiac protection through induce multiple signal pathways and other unknown mechanisms that actually injuries resistance to acute ischemia and reduce the injuries caused by ischemia Acute and decreased cellular damage in the cardiac tissue. Therefore, the expected accumulation chemokine tissue levels in the training-myocardial infraction group may be statistically insignificant.