Cardioprotective Effects Of Exercise Training Research Articles

Exercise training counteracts the cardiac metabolic remodelling induced by experimental pulmonary arterial hypertension

Exercise training provides several cardiovascular benefits in both physiological and pathological conditions; however, its use as a therapeutic tool for pulmonary arterial hypertension (PAH) has been poorly explored. This study aimed to extend the comprehension of the cardioprotective effects of exercise training in the set of PAH focusing on the metabolic changes promoted by exercise in the right ventricle (RV). The monocrotaline animal model of PAH was used and male Wistar rats were submitted to two weeks of treadmill exercise training (5 days/week, 60 min/day, 25 m/min) following disease establishment. Trained rats showed an improved diastolic function (lower end-diastolic pressure and tau) despite the presence of cardiac overload (increased peak systolic pressure, end-diastolic pressure and arterial elastance). This enhanced hemodynamic response was paralleled by an increased uptake of glucose to cardiomyocytes through glucose transporter type 4 (GLUT4) followed by increased lactate dehydrogenase (LDH) activity. Exercise did not reverse the decrease of fatty acid oxidation related to PAH but increased the content of the transcription factors peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Two weeks of exercise did not modulate the changes in amino acid metabolism secondary to PAH. Our work suggests that continuous aerobic exercise of moderate intensity, despite its short-term duration and application in a late stage of the disease, supports the RV response to PAH by promoting a shift in the cardiac metabolic phenotype.

Exercise Training Ameliorates Cardiac Aging Of Mice Through Activating Apelin/apj System

PURPOSE: Apelin/APJ system is known to improve cardiovascular disease. Exercise training has been associated with benefits against cardiac diseases and aging associated disorders. Our previous research showed that the serum Apelin levels decreased with age and exogenous Apelin intervention or overexpression of its receptor APJ could reverse the aging phenotype in D-galactose-induced aging cardiomyocytes. Herein we investigated the role Apelin/APJ system played in exercise training ameliorates cardiac aging. METHODS: The aging heart was simulated in 24 weeks-old senescence-accelerated mice. Mice were subjected to 6 weeks treadmill training, and treated with or without intraperitoneal injection of the apelin receptor antagonist - F13A 75ug/kg per day during training. The effects of treadmill training on circulating Apelin, myocardial Apelin / APJ, cardiac aging phenotype and mitochondrial autophagy were evaluated. RESULTS: Exercise training reduced weight loss, myocardial fibrosis and cardiac expression of aging biomarkers (p16, p53 and p21) in aged mice. In addition, exercise training increased the expression of Apelin and APJ in cardiomyocytes and maintained mitochondrial homeostasis, as evidenced by expression of mitochondrial related proteins (PGC-1α, CPT1A, PINK1, Parkin, Drp-1 and fis-1). The cardioprotective effects of exercise training were weakened by inhibition of the Apelin/APJ system. CONCLUSIONS: Taken together, our research showed that exercise training ameliorated phenotype of cardiac aging and disruption of mitochondrial homeostasis through activating the Apelin/APJ system. Hence, pharmacological activation of the Apelin/APJ system may prove to be a promising prevention against aging related heart disease especially in subjects with intolerance of exercise.

Exercise Training Protects Against Heart Failure Via Expansion of Myeloid-Derived Suppressor Cells Through Regulating IL-10/STAT3/S100A9 Pathway.

Exercise training (ET) has a protective effect on the progression of heart failure, however, the specific mechanism has not been fully explored. Myeloid-derived suppressor cells (MDSCs) are a group of myeloid-derived immunosuppressive cells, which showed a protective effect in the progression of heart failure. Thus, we hypothesized that the protective effect of ET on heart failure may be related to the infiltration of MDSCs. C57BL/6 mice were made to run on a treadmill 6× a week for 4 weeks followed by isoproterenol injection from third week. Heart function was evaluated by echocardiography and the proportion of MDSCs was detected by flow cytometry. Hypertrophic markers, cardiac fibrosis, and inflammatory factors were detected by real-time PCR, ELISA, histological staining, and Western blot. ET treatment in isoproterenol-induced heart failure mice (n=7) enhanced cardiac function (57% increase in FS%, P=0.002) and improved morphological changes compared with isoproterenol mice (n=17). ET further caused 79% increasing in cardiac MDSCs in isoproterenol mice (P<0.001). In addition, depletion of MDSCs by 5-Fluorouracil blunted the cardio-protective effect of ET. T-cell proliferation assay showed that ET did not affect the suppressive activity of MDSCs. Furthermore, we found that ET activated the secretion of IL (interleukin)-10 by macrophages in isoproterenol mice. MDSCs expansion and cardio protection was not present in tamoxifen-inducible macrophage-specific IL-10 knockout mice. Western blot results confirmed that IL-10 regulated the differentiation of MDSCs through the translocation of p-STAT3 (signal transducer and activator of transcription 3)/S100A9 (S100 calcium-binding protein A9) to the nucleus. ET could increase MDSCs by stimulating the secretion of IL-10 from macrophage, which was through IL-10/STAT3/S100A9 signaling pathway, thereby achieving the role of heart protection.

Increased protein S-nitrosylation in mitochondria: a key mechanism of exercise-induced cardioprotection.

Endothelial nitric oxide synthase (eNOS) activation in the heart plays a key role in exercise-induced cardioprotection during ischemia-reperfusion, but the underlying mechanisms remain unknown. We hypothesized that the cardioprotective effect of exercise training could be explained by the re-localization of eNOS-dependent nitric oxide (NO)/S-nitrosylation signaling to mitochondria. By comparing exercised (5days/week for 5weeks) and sedentary Wistar rats, we found that exercise training increased eNOS level and activation by phosphorylation (at serine 1177) in mitochondria, but not in the cytosolic subfraction of cardiomyocytes. Using confocal microscopy, we confirmed that NO production in mitochondria was increased in response to H2O2 exposure in cardiomyocytes from exercised but not sedentary rats. Moreover, by S-nitrosoproteomic analysis, we identified several key S-nitrosylated proteins involved in mitochondrial function and cardioprotection. In agreement, we also observed that the increase in Ca2+ retention capacity by mitochondria isolated from the heart of exercised rats was abolished by exposure to the NOS inhibitor L-NAME or to the reducing agent ascorbate, known to denitrosylate proteins. Pre-incubation with ascorbate or L-NAME also increased mitochondrial reactive oxygen species production in cardiomyocytes from exercised but not from sedentary animals. We confirmed these results using isolated hearts perfused with L-NAME before ischemia-reperfusion. Altogether, these results strongly support the hypothesis that exercise training increases eNOS/NO/S-nitrosylation signaling in mitochondria, which might represent a key mechanism of exercise-induced cardioprotection.

How can exercise reduce cardiovascular disease risk? A primer for the clinician

Despite advances in drug development and medical treatments, cardiovascular diseases (CVDs) remain a leading cause of mortality across the globe. Fortunately, CVD can be delayed by engaging in appropriate lifestyle behaviors. An abundance of epidemiological evidence supports a direct association between increased levels of physical activity or cardiovascular fitness and reduced premature CVD morbidity and mortality. These data have been used as the basis for many medical organizations to issue physical activity guidelines to citizens to improve physical activity participation and, ultimately, reduce the risk of CVDs and other chronic diseases. Despite these efforts, physical activity participation around the globe remains low. The medical professional is well suited to promote exercise as a preventative treatment for CVD, although promotion efforts may be less effective without a clear understanding of the mechanisms through which exercise confers cardioprotection. Thus, the purpose of this review is to highlight the cardioprotective effects of exercise training and to explore the underlying mechanistic pathways that might explain these benefits. The review will focus on those physiological pathways that are directly involved in atherosclerotic disease development. They include hypercholesterolemia, hypertension, chronic inflammation, and insulin resistance.

Involvement of Sirtuins and Klotho in Cardioprotective Effects of Exercise Training Against Waterpipe Tobacco Smoking-Induced Heart Dysfunction.

Despite its negative effect on the cardiovascular system, waterpipe smoking (WPS) is currently popular worldwide, especially among youth. This study investigated the effects of moderate endurance exercise on heart function of rats exposed to WPS and its possible mechanism. The animals were randomly divided into four groups: control group (CTL), the exercise group (Ex) which trained for 8 weeks, the waterpipe tobacco smoking group (S) exposed to smoke inhalation (30 min per day, 5 days each week, for 8 weeks), and the group that did exercise training and received waterpipe tobacco smoke inhalation together (Ex + S). One day after the last session of Ex and WPS, cardiac pressures and functional indices were recorded and calculated. The levels of SIRT1, SIRT3, Klotho, Bax, and Bcl-2 in the serum and heart, the expression of phosphorylated GSK3β of heart tissue, and cardiac histopathological changes were assessed. WPS reduced systolic pressure, +dP/dt max, -dP/dt max, and heart contractility indices (P < 0.001 vs. CTL) and increased cardiac tissue lesions (P < 0.05 vs. CTL) and end diastolic pressure and Tau index (P < 0.001 vs. CTL) of the left ventricle. Exercise training normalized the left ventricular end diastolic pressure, +dP/dt max, and contractility index. Also, exercise improved the levels of SIRT1, SIRT3, Klotho, and Bcl-2 and reduced Bax level in the heart. The findings showed that WPS causes left ventricular dysfunction. Moderate exercise prevented WPS-induced heart dysfunction partly through its anti-apoptotic features and activation of the sirtuins and Klotho pathways.

Exercise Training Preserves Myocardial Strain and Improves Exercise Tolerance in Doxorubicin-Induced Cardiotoxicity.

Doxorubicin causes cardiotoxicity and exercise intolerance. Pre-conditioning exercise training seems to prevent doxorubicin-induced cardiac damage. However, the effectiveness of the cardioprotective effects of exercise training concomitantly with doxorubicin treatment remains largely unknown. To determine whether low-to-moderate intensity aerobic exercise training during doxorubicin treatment would prevent cardiotoxicity and exercise intolerance, we performed exercise training concomitantly with chronic doxorubicin treatment in mice. Ventricular structure and function were accessed by echocardiography, exercise tolerance by maximal exercise test, and cardiac biology by histological and molecular techniques. Doxorubicin-induced cardiotoxicity, evidenced by impaired ventricular function, cardiac atrophy, and fibrosis. Exercise training did not preserve left ventricular ejection fraction or reduced fibrosis. However, exercise training preserved myocardial circumferential strain alleviated cardiac atrophy and restored cardiomyocyte cross-sectional area. On the other hand, exercise training exacerbated doxorubicin-induced body wasting without affecting survival. Finally, exercise training blunted doxorubicin-induced exercise intolerance. Exercise training performed during doxorubicin-based chemotherapy can be a valuable approach to attenuate cardiotoxicity.

Cardioprotective effects of exercise training on doxorubicin-induced cardiomyopathy: a systematic review with meta-analysis of preclinical studies

Doxorubicin (DOX)-induced cardiotoxicity in chemotherapy is a major treatment drawback. Clinical trials on the cardioprotective effects of exercise in cancer patients have not yet been published. Thus, we conducted a systematic review and meta-analysis of preclinical studies for to assess the efficacy of exercise training on DOX-induced cardiomyopathy. We included studies with animal models of DOX-induced cardiomyopathy and exercise training from PubMed, Web of Sciences and Scopus databases. The outcome was the mean difference (MD) in fractional shortening (FS, %) assessed by echocardiography between sedentary and trained DOX-treated animals. Trained DOX-treated animals improved 7.40% (95% CI 5.75–9.05, p < 0.001) in FS vs. sedentary animals. Subgroup analyses revealed a superior effect of exercise training execution prior to DOX exposure (MD = 8.20, 95% CI 6.27–10.13, p = 0.010). The assessment of cardiac function up to 10 days after DOX exposure and completion of exercise protocol was also associated with superior effect size in FS (MD = 7.89, 95% CI 6.11–9.67, p = 0.020) vs. an echocardiography after over 4 weeks. Modality and duration of exercise, gender and cumulative DOX dose did were not individually associated with changes on FS. Exercise training is a cardioprotective approach in rodent models of DOX-induced cardiomyopathy. Exercise prior to DOX exposure exerts greater effect sizes on FS preservation.

Cardiac, Autonomic, and Cardiometabolic Impact of Exercise Training in Spinal Cord Injury: A QUALITATIVE REVIEW.

Direct and indirect effects of spinal cord injury lead to important cardiovascular (CV) complications that are further increased by years of injury and the process of "accelerated aging." The present review examines the current evidence in the literature for the potential cardioprotective effect of exercise training in spinal cord injury. PubMed and Web of Science databases were screened for original studies investigating the effect of exercise-based interventions on aerobic capacity, cardiac structure/function, autonomic function, CV function, and/or cardiometabolic markers. We compared the effects in individuals <40 yr with time since injury <10 yr with those in older individuals (≥40 yr) with longer time since injury (≥10 yr), reasoning that the two can be considered individuals with low versus high CV risk factors. Studies showed similar exercise effects in both groups (n = 31 in low CV risk factors vs n = 15 in high CV risk factors). The evidence does not support any effect of exercise training on autonomic function but does support an increased peripheral blood flow, improved left ventricular mass, higher peak cardiac output, greater lean body mass, better antioxidant capacity, and improved endothelial function. In addition, some evidence suggests that it can result in lower blood lipids, systemic inflammation (interleukin-6, tumor necrosis factor α, and C-reactive protein), and arterial stiffness. Training intensity, volume, and frequency were key factors determining CV gains. Future studies with larger sample sizes, well-matched groups of subjects, and randomized controlled designs will be needed to determine whether high-intensity hybrid forms of training result in greater CV gains.

Exercise, cancer and cardiovascular disease: what should clinicians advise?

Cardiovascular disease is one of the leading causes of morbidity and mortality in persons with cancer. The elevated risk is thought to derive from the combination of cardiovascular risk factors and direct cardiotoxicity from cancer therapies. Exercise may be a potential strategy to counteract these toxicities and maintain cardiovascular reserve. In this article, we review the evidence for the potential cardioprotective effects of exercise training in cancer patients before, during, and following treatment. We also propose a patient-tailored approach for the development of targeted prescriptions based on individual exercise capacity and cardiovascular reserve.

12-Week Exercise Training, Independent of the Type of Exercise, Attenuates Endothelial Ischaemia-Reperfusion Injury in Heart Failure Patients.

Introduction: Reperfusion is required to salvage ischaemic tissue, but also causes further damage (i.e., ischaemia/reperfusion-injury). Heart failure patients reveal exaggerated ischaemia/reperfusion-injury, whilst traditional ischaemic preconditioning cannot prevent ischaemia/reperfusion-injury. Exercise training may be a more powerful preconditioning stimulus, especially high-intensity interval training given the similarities with ischaemic preconditioning. Therefore, we examined the impact of 12-week continuous training vs. high-intensity interval training on brachial artery endothelial ischaemia/reperfusion-injury in heart failure patients New York Heart Association-class II-III.Methods: Twenty heart failure patients (male:female 19:1, 64 ± 8 years, ejection fraction 38 ± 6%) were allocated to 12-weeks of high-intensity interval training (10∗1-min 90% maximal workload – 2.5-min 30% maximal workload) or continuous training (30-min 60–75% maximal workload). Before and after the intervention, we measured brachial artery endothelial function with flow-mediated dilation (FMD) before and after ischaemia/reperfusion (5-min ischemic exercise, 15-min reperfusion).Results: Ischaemia/reperfusion caused a significant decline in FMD (continuous training (n = 10): 5.2 ± 2.5 to 3.4 ± 1.6%, high-intensity interval training (n = 10): 5.3 ± 2.6 to 3.5 ± 1.6%, P = 0.01), which was not different between groups (P > 0.05). Training improved maximal workload and fitness (P < 0.05), with no differences between groups (P > 0.05). Exercise training did not alter FMD (P > 0.05), whilst ischaemia/reperfusion did not impair FMD after exercise training (continuous training: 4.8 ± 3.0 to 4.2 ± 2.3%, high-intensity interval training: 4.7 ± 2.5 to 3.8 ± 2.3%, P > 0.05). No changes were found in FMD before or after ischaemia/reperfusion after 12-weeks in controls (n = 9).Conclusion: We found that 12-week exercise training in heart failure patients mitigated endothelial ischaemia-reperfusion injury, an effect independent of the type of exercise. These changes may contribute to the cardioprotective effects of exercise training, whilst our findings highlight the potency of exercise as a preconditioning stimulus.

PL - 027 Up-regulation of NRG1 improves cardiac repair in zebra fish and involved in the cardioprotective effects of exercise training in rats of myocardial infarction

Objective Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Exercise training could improve cardiac function following MI. However, the mechanisms are still not well-known. Neuregulin 1 (NRG1)plays an important role in heart development and regeneration.In this study, we investigated the effect of NRG1 on cardiac regeneration in a zebrafish model, detected whether exercise could improve cardiac function through regulating NRG1 expression in infarcted heart and explore the possible role of up-regulation of NRG1 in skeletal muscle play in the cardioprotective effects in rats with MI.&#x0D; Methods Transgenic zebrafish line, cmlc2:CreERandβ-act2:BSNrg1,wereusedto study the effect of NRG1 on heart growth and regeneration after injury. PCNA was detected by immunofluorescence staining andmRNAexpression of gata4, nkx2.5, tbx5, smyd1b, hsp90α and murf were tested by RT-PCR.Sprague-Dawley rats were used to establish MI model and underwent fourweeks of exercise training (ET) or pAAV-{dMCK promoter}rNRG1-eGFP intervention.AG1478 was used asan inhibitor of NRG1/ErbBs signaling pathway. Cardiac function and structure,cardiomyocyte proliferation and NRG1 expression were detected in the heart or skeletal.&#x0D; Results Cardiac-specific overexpression of NRG1 induced cardiac hypertrophy and cardiomyocyte proliferation, regulated the mRNA expression of gata4, nkx2.5, tbx5, smyd1b, hsp90α andmurf in uninjuriedzebrafish, and promote cardiac repair and regeneration after injury in the zebrafish.Exercise activated NRG1/ErbBs signaling pathway, improved cardiac remodeling and heart function, enhanced cardiomyocyte proliferation, reduced cardiomyocyte apoptosis, ROS level and MuRF1 protein expression in rats with MI. BlockingErbB signaling attenuated the ET-induced cardioprotection effects in rat with MI.up-regulation of NRG1 expression in skeletal muscle could increase the protein level of NRG1 in serum and infarcted heart, improve cardiomyocyte proliferation and reduce the level of cardiac fibrosis, finally promote cardiac function.&#x0D; Conclusions Up-regulation of NRG1 expression in the heart or skeletal musclemay be one of the underlying mechanisms of thebeneficial effects of exercise training following MI.

κ-opioid receptor is involved in the cardioprotection induced by exercise training.

The present study was designed to test the hypothesis that exercise training elicited a cardioprotective effect against ischemia and reperfusion (I/R) via the κ-opioid receptor (κ-OR)-mediated signaling pathway. Rats were randomly divided into four groups: the control group, the moderate intensity exercise (ME) group, the high intensity exercise (HE) group, and the acute exercise (AE) group. For the exercise training protocols, the rats were subjected to one week of adaptive treadmill training, while from the second week, the ME and HE groups were subjected to eight weeks of exercise training, and the AE group was subjected to three days of adaptive treadmill training and one day of vigorous exercise. After these protocols, the three exercise training groups were divided into different treatment groups, and the rats were subjected to 30 min of ischemia and 120 min of reperfusion. Changes in infarct size and serum cTnT (cardiac troponin T) caused by I/R were reduced by exercise training. Moreover, cardiac dysfunction caused by I/R was also alleviated by exercise training. These effects of exercise training were reversed by nor-BNI (a selective κ-OR antagonist), Compound C (a selective AMPK inhibitor), Akt inhibitor and L-NAME (a non-selective eNOS inhibitor). Expression of κ-OR and phosphorylation of AMPK, Akt and eNOS were significantly increased in the ME, HE and AE groups. These findings demonstrated that the cardioprotective effect of exercise training is possibly mediated by the κ-OR-AMPK-Akt-eNOS signaling pathway.

Impact of lifelong exercise training on endothelial ischemia-reperfusion and ischemic preconditioning in humans.

Reperfusion is essential for ischemic tissue survival, but causes additional damage to the endothelium [i.e., ischemia-reperfusion (I/R) injury]. Ischemic preconditioning (IPC) refers to short repetitive episodes of ischemia that can protect against I/R. However, IPC efficacy attenuates with older age. Whether physical inactivity contributes to the attenuated efficacy of IPC to protect against I/R injury in older humans is unclear. We tested the hypotheses that lifelong exercise training relates to 1) attenuated endothelial I/R and 2) maintained IPC efficacy that protects veteran athletes against endothelial I/R. In 18 sedentary male individuals (SED, <1 exercise h/wk for >20 yr, 63 ± 7 yr) and 20 veteran male athletes (ATH, >5 exercise h/wk for >20 yr, 63 ± 6 yr), we measured brachial artery endothelial function with flow-mediated dilation (FMD) before and after I/R. We induced I/R by 20 min of ischemia followed by 20 min of reperfusion. Randomized over 2 days, participants underwent either 35-min rest or IPC (3 cycles of 5-min cuff inflation to 220 mmHg with 5 min of rest) before I/R. In SED, FMD decreased after I/R [median (interquartile range)]: [3.0% (2.0-4.7) to 2.1% (1.5-3.9), P = 0.046] and IPC did not prevent this decline [4.1% (2.6-5.2) to 2.8% (2.2-3.6), P = 0.012]. In ATH, FMD was preserved after I/R [3.0% (1.7-5.4) to 3.0% (1.9-4.1), P = 0.82] and when IPC preceded I/R [3.2% (1.9-4.2) to 2.8% (1.4-4.6), P = 0.18]. These findings indicate that lifelong exercise training is associated with increased tolerance against endothelial I/R. These protective, preconditioning effects of lifelong exercise against endothelial I/R may contribute to the cardioprotective effects of exercise training.

Key role of endothelium in the eNOS-dependent cardioprotection with exercise training

Modulation of endothelial nitric oxide synthase (eNOS) activation is recognized as a main trigger of the cardioprotective effects of exercise training on heart vulnerability to ischemia-reperfusion (IR). However, this enzyme is expressed both in coronary endothelial cells and cardiomyocytes and the contribution of each one to such cardioprotection has never been challenged. The aim of this study was to investigate the role of eNOS from the cardiomyocytes vs. the endothelium in the exercise cardioprotection. Male Wistar rats were assigned to a chronic aerobic training (Ex) (vs. sedentary group; Sed) and we investigated the role of eNOS in the effects of exercise on sensitivity to IR or anoxia-reoxygenation (A/R) at whole heart, isolated cardiomyocytes and left coronary artery (LCA) levels. We observed that exercise increased eNOS activation (Ser1177 phosphorylation) and protein S-nitrosylation in whole heart but not at cardiomyocyte level, suggesting the specific target of endothelial cells by exercise. Consistently, in isolated cardiomyocytes submitted to the A/R procedure, exercise reduced cell death and improved cells contractility, but independently of the eNOS pathway. Next, to evaluate the contribution of endothelial cells in exercise cardioprotection, LCA were isolated before and after an IR procedure performed on Langendorff hearts. Exercise improved basal relaxation sensitivity to acetylcholine and markedly reduced the alteration of endothelium-dependent coronary relaxation induced by IR. Furthermore, inactivation of coronary endothelial cells activity just before IR, obtained with a bolus of Triton X-100, totally suppressed cardioprotective effects of exercise on both left ventricular functional recovery after IR and infarct size, whereas no effect of Triton X-100 was observed in Sed group. In conclusion, these results show that coronary endothelial cells rather than cardiomyocytes play a key role in the eNOS-dependent cardioprotection of exercise.

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity.

Doxorubicin is one of the most commonly used cytotoxic anticancer drugs against several cancers. Although a highly effective anticancer drug, the clinical use of doxorubicin is severely limited by its cardiotoxicity which results in morbidity, poor quality of life, and premature mortality. Only very few clinically accepted methods to minimize doxorubicin-induced cardiac injury are available today, but none of them have proven to be completely successful. Due to limited alternative strategies, a number of potential cardioprotective therapies are currently being investigated for treating and/or preventing doxorubicin-induced cardiotoxicity. Of these potential strategies, aerobic exercise training is the only nonpharmacologic strategy that shows a great deal of promise. Although there are no published human clinical trials, evidence from numerous animal studies suggests that aerobic exercise training, administered prior to, during and/or following doxorubicin therapy, is protective against doxorubicin-induced cardiac injury. Protective properties of exercise training against the cardiotoxicity of doxorubicin have been attributed to a number of potential molecular mechanisms including: enhancing the production of endogenous antioxidant machineries; regulating proapoptotic signaling; stimulating the release, mobilization and homing of cardiac progenitor cells; limiting myocyte turnover; eliciting favorable adaptations in myocardial calcium handling and preventing calcium overload; modulating cardiac AMPK activity; downregulating cardiac autophagy/lysosomal signaling; and reducing myocardial doxorubicin accumulation. Further preclinical and clinical research is needed to decipher and refine the molecular mechanisms underlying the cardioprotective effects of exercise training, as well as to define the nature and magnitude of the effect of exercise on doxorubicin-induced cardiotoxicity in cancer patients.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity

Doxorubicin is one of the most commonly used cytotoxic anticancer drugs against several cancers.  Although a highly effective anticancer drug, the clinical use of doxorubicin is severely limited by its cardiotoxicity which results in morbidity, poor quality of life, and premature mortality.  Only very few clinically accepted methods to minimize doxorubicin-induced cardiac injury are available today, but none of them have proven to be completely successful.  Due to limited alternative strategies, a number of potential cardioprotective therapies are currently being investigated for treating and/or preventing doxorubicin-induced cardiotoxicity.  Of these potential strategies, aerobic exercise training is the only nonpharmacologic strategy that shows a great deal of promise.  Although there are no published human clinical trials, evidence from numerous animal studies suggests that aerobic exercise training, administered prior to, during and/or following doxorubicin therapy, is protective against doxorubicin-induced cardiac injury.  Protective properties of exercise training against the cardiotoxicity of doxorubicin have been attributed to a number of potential molecular mechanisms including:  enhancing the production of endogenous antioxidant machineries; regulating proapoptotic signaling; stimulating the release, mobilization and homing of cardiac progenitor cells; limiting myocyte turnover; eliciting favorable adaptations in myocardial calcium handling and preventing calcium overload; modulating cardiac AMPK activity; downregulating cardiac autophagy/lysosomal signaling; and reducing myocardial doxorubicin accumulation.  Further preclinical and clinical research is needed to decipher and refine the molecular mechanisms underlying the cardioprotective effects of exercise training, as well as to define the nature and magnitude of the effect of exercise on doxorubicin-induced cardiotoxicity in cancer patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Exercise does not activate the β3 adrenergic receptor–eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice

Obesity and diabetes are associated with higher cardiac vulnerability to ischemia-reperfusion (IR). The cardioprotective effect of regular exercise has been attributed to β3-adrenergic receptor (β3AR) stimulation and increased endothelial nitric oxide synthase (eNOS) activation. Here, we evaluated the role of the β3AR-eNOS pathway and NOS isoforms in exercise-induced cardioprotection of C57Bl6 mice fed with high fat and sucrose diet (HFS) for 12weeks and subjected or not to exercise training during the last 4 weeks (HFS-Ex). HFS animals were more sensitive to in vivo and ex vivo IR injuries than control (normal diet) and HFS-Ex mice. Cardioprotection in HFS-Ex mice was not associated with increased myocardial eNOS activation and NO metabolites storage, possibly due to the β3AR-eNOS pathway functional loss in their heart. Indeed, a selective β3AR agonist (BRL37344) increased eNOS activation and had a protective effect against IR in control, but not in HFS hearts. Moreover, iNOS expression, nitro-oxidative stress (protein s-nitrosylation and nitrotyrosination) and ROS production during early reperfusion were increased in HFS, but not in control mice. Exercise normalized iNOS level and reduced protein s-nitrosylation, nitrotyrosination and ROS production in HFS-Ex hearts during early reperfusion. The iNOS inhibitor 1400W reduced in vivo infarct size in HFS mice to control levels, supporting the potential role of iNOS normalization in the cardioprotective effects of exercise training in HFS-Ex mice. Although the β3AR-eNOS pathway is defective in the heart of HFS mice, regular exercise can protect their heart against IR by reducing iNOS expression and nitro-oxidative stress.

Breast cancer treatment-associated cardiovascular toxicity and effects of exercise countermeasures.

Advances in breast cancer treatment have improved disease-free survival and overall survival in women with early-stage breast cancer. However, these improvements may be attenuated by the adverse cardiovascular effects associated with breast cancer adjuvant therapy. Exercise may be a potential strategy to counteract these toxicities. The purpose of this paper is to provide an overview on the adverse cardiovascular effects of breast cancer therapy as well as the evidence supporting the potential cardioprotective effects of exercise training in breast cancer patients during and after treatment. We will also discuss research gaps and avenues for future research.

Cardioprotective Effect of Exercise Training in Heart Failure Rats: Exercise Training Reduces Oxidative Stress Induced Nuclear Genomic Fragmentation

Alterations in energy metabolism are hallmarks of heart failure (HF) following myocardial infarction (MI). The failing heart is commonly described as an energy-starved engine that has run out of fuel, and myocardial energetics is therefore a topic of considerable interest. Markers of oxidative stress are elevated in HF and have been correlated with myocardial dysfunction. Increased oxidative stress can induce DNA damage, and the main repair mechanism of oxidative DNA damage is Base excision repair (BER) and Single strand break repair (SSBR). Defects in SSBR in post-mitotic cells have been associated with human diseases. Exercise training is an effective treatment for HF. Therefore we aimed to investigate the effect of exercise training on the nuclear genomic integrity in HF rats.MI was induced in 30 female Sprague Dawley rats by surgical ligation of the descending coronary artery. HF was present 4 weeks after ligation. HF rats were then randomized to remain sedentary (n=10) or exposed to either moderate (n=10) or high intensity (n=10) aerobic interval training. Sham sedentary rats (n=10) acted as controls. After 6 weeks of exercise training, H2O2 induced genomic DNA fragmentation was studied in isolated left ventricular cardiomyocytes through an alkaline single cell gel electrophoresis assay. Cardiomyocytes from HF sedentary rats had an increase in H2O2 induced genomic fragmentation by 29% relative to sham, exercise training reduced the genomic fragmentation towards sham levels. 31P NMR experiments revealed reduced PCr concentration in HF and exercise training did not change the PCr levels. However, both moderate- and high intensity training resulted in an increase in cardiac ATP concentration in HF rats. Exercise training seems to induce a cardioprotective effect to increased oxidative stress in HF rats and possibly affects BER/SSBR pathways.