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Working out the heart: Functional remodeling by endurance exercise training
Journal of Molecular and Cellular Cardiology 60 (2013) 47–49
Contents lists available at SciVerse ScienceDirect
Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Editorial
Working out the heart: Functional remodeling by endurance exercise training
Physical training, particularly in the case of aerobic exercise, has been shown to produce several physiological changes, among which are increase in the maximal oxygen uptake and general physical fitness, improvement in the sensitivity of some visceral reflexes, and decrease in the sympathetic drive to the heart, accompanied by increase in the vagal tone (e.g., [1,2]). The reported effects of exercise on the heart in the absence of cardiovascular affections include enhancement of contractility, acceleration of Ca 2+ transient and/or contraction kinetics, reduction of the oxygen requirements at increasing workloads, ischemic protection, and induction of anti-oxidant enzymes and chaperones [2–7]. Depending on the exercise modality, intensity and duration, myocardial hypertrophy may ensue. However, this so-called physiological hypertrophy differs from the hypertrophic growth that usually develops in response to chronic arterial hypertension and myocardial infarction. The latter is usually accompanied by increased expression of cell stress biomarkers (e.g., atrial natriuretic peptide), fibrosis, relative capillary rarefaction and greater propensity to arrhythmias, which are not observed in the physiological type of hypertrophy [8–11]. Thus, although hypertrophic growth is an adaptive response of the heart to increased hemodynamic load, physiological hypertrophy and pathological hypertrophy are quite distinct regarding the signaling pathway, morphological pattern, molecular and functional alterations, and evolution, as compensated pathological hypertrophy may progress to heart failure [2,8,9]. Nevertheless, it should be noticed that cardiac dysfunction and some phenotypic changes commonly observed in pathological hypertrophy can be induced by very intense and/or prolonged physical activity [12]. Would these 2 types of cardiac remodeling be superimposable? In the current issue of Journal of Molecular and Cellular Cardiology, Carneiro-Júnior et al., in their article The benefits of endurance training in cardiomyocyte function in hypertensive rats are reversed within four weeks of detraining [13], contribute to shed light on this issue reporting the molecular and functional effects of low-intensity endurance training (running) on the heart of spontaneously hypertensive rats, in which development of hypertension is associated with heightened sympathetic activity [14]. In their study, the authors observed that training, although not effective at normalizing the blood pressure, was able to reverse the myocardial overexpression of stress markers, one of the hallmarks of the pathologically hypertrophied heart. Their results are in agreement with previous data that indicate that different modalities of endurance training can lead to morphological, molecular and functional conversion of the pathological to the physiological hypertrophy phenotype in this hypertension model [15,16]. It should be pointed out, however, that this has not always been the case: failure of chronic exercise at improving cardiac function and producing beneficial effects was reported for 0022-2828/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.yjmcc.2013.02.017
compensated and decompensated hypertrophy induced by aortic constriction [17]. Carneiro-Júnior et al. [13] also described increased amplitude and acceleration of the timecourse of electrically-evoked Ca 2+ transients and contractions in myocytes from trained normotensive and hypertensive animals. These changes, which were correlated with heightened exercise capacity, are reported both in the absence or in the presence of cardiovascular affections [2,4]. While the increase in contraction amplitude could be partially explained by enhanced myofilament sensitivity to Ca 2+ after training [2], changes in cell Ca 2+ handling might significantly contribute to the improvement of the contractile activity. Most authors have observed that long-term exercise training increases the ventricular expression of the sarcoplasmic reticulum (SR) Ca 2+-ATPase (SERCA) and/or the ratio of SERCA and phospholamban, its endogenous negative regulator [2,4,13,15]. Such alterations should result in increased SERCA activity, which could explain the concurrently observed faster decline of Ca 2+ transients, as SERCA is the main pathway for removal of cytosolic Ca 2+ in mammalian myocardium [18]. From the physiological point of view, upregulation of SERCA expression and activity should permit adequate ventricular filling at higher heart rates, which are reached during exercise, thus allowing that cardiac output be compatible with the greater metabolic requirement of the tissues. This is possibly the reason why the rate of decline of the Ca2+ transients and SERCA protein levels have shown correlation with exercise capacity [13,19]. Additionally, augmented SERCA activity may result in increase in the SR Ca2+ content. This change might greatly impact the amount of Ca2+ released from the organelle and made available for the myofilaments, mostly because the fraction of the SR Ca2+ content that is released at systole (fractional SR Ca2+ release) is determined, in a positive and non-linear fashion, by the amount of Ca2+ stored in the SR [20,21]. Although the excitation–contraction coupling efficiency has not been examined by Carneiro-Júnior et. al. [13], such a mechanism might explain the greater Ca2+ transients observed by them and other authors, considering that the SR is the source of most of the Ca2+ that activates contraction. It still remains to be established whether exercise training and its associated increase in myocardial SERCA expression lead to greater SR Ca2+ loading and fractional release. In the case of hypertension models, the amount of released Ca 2+ or the fractional release was found to be enhanced during the early phases of compensated hypertrophy [22], whereas it tends to decrease in the chronic state and progression to heart failure [23,24]. In this respect, it is noteworthy that, under unphysiological conditions (e.g., arterial hypertension, myocardial infarction), SERCA activity and expression are usually decreased [25], in contrast to its consistent enhancement reported after exercise training. This divergence in the two kinds of hypertrophic remodeling might be at least
48
Editorial
partially dependent on the hemodynamic and neurohumoral conditions in each situation. Increase in the mechanical load was shown to result in acute myocardial SERCA upregulation. However, increased afterload and/or prolonged β-adrenergic stimulation (which is expected to occur in chronic hypertension, for instance) also increases the cardiac expression of brain natriuretic peptide (BNP). Evidence indicates that BNP upregulation, which occurs after aortic constriction and in the failing myocardium, seems to be implicated in the suppression of load-induced SERCA upregulation [25,26]. Thus, it is possible that the reversal of the overexpression of natriuretic peptides by chronic exercise, as reported by Carneiro-Júnior et al. [13] and others, may play a role in the SERCA upregulation observed in the hearts of trained animals. Because training did not diminish the blood pressure in hypertensive rats, it is possible that the decrease in basal sympathetic tone or the increase in venous return during the exercise sessions might be related to the augmented SERCA expression. The increase in end-diastolic ventricular volume during exercise might also be linked to redox RyR regulation in response to stretch [27]. Ca 2 + influx also is a key factor in excitation–contraction coupling. Even for unchanged SR Ca 2+ load, the fractional SR Ca 2+ release can be enhanced by increase in the trigger of the release process, namely, the L-type Ca 2+ current [20]. How exercise affects this trigger is a controversial issue and requires better clarification, as either increase, decrease or no change in the peak density of this current has been reported after aerobic exercise training [11,28,29]. Another potential mechanism affecting excitation–contraction coupling is the direct regulation of the SR Ca 2+ release channel (or ryanodine receptor, RyR). Little information is available on the effects of physical activity on RyR function and regulation. Sánchez et al. [5] described exercise-induced increase in myocardial NADPH oxidase activity, RyR S-glutathionylation and in the rate of Ca 2+-induced Ca 2+ release after exercise, which suggests involvement of RyR regulation by reactive oxygen species. This mechanism might mediate stretch-dependent regulation of SR Ca 2+ release [27]. While available evidence points out that exercise training can lead to myocardial remodeling associated with stimulation of Ca 2+ cycling, and enhanced contractility and exercise capacity, it also indicates that this remodeling depends on the persistence of its inductor, namely, the regular physical activity. Two weeks detraining are sufficient for attenuation of the ventricular hypertrophy, the enhanced aerobic capacity, and the changes in Ca 2+ transients and contraction brought about by long-term (8–13 weeks) endurance training. After 4 weeks of exercise cessation, such changes are no longer apparent [2,13]. These observations indicate the remarkable plasticity of myocardial regulation and the reversible nature of this type of remodeling of the myocardium, which requires continuous recruitment of regulatory mechanisms for its maintenance. The growing knowledge on the cardiac effects of exercise has revealed important aspects of the dynamic and complex nature of the regulation of the myocardium, at molecular and functional levels. At the same time, it has pointed out the clinical relevance and potential of regular, moderate physical activity as a valuable non-pharmacological alternative for prevention of cardiovascular dysfunctions, as well as for improvement of cardiac performance of the diseased myocardium. Disclosures None. Funding This work was funded by grant of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—302996/2011-7 to JWMB).
References [1] De Angelis K, Wichi RB, Jesus WR, Moreira ED, Morris K, Krieger EM, et al. Exercise training changes autonomic cardiovascular balance in mice. J Appl Physiol 2004;96:2174–8. [2] Kemi OJ, Wisløff U. Mechanisms of exercise-induced improvements in the contractile apparatus of the mammalian myocardium. Acta Physiol (Oxf) 2010;199: 425–39. [3] Reger PO, Barbe MF, Amin M, Renna BF, Hewston LA, MacDonnell SM, et al. Myocardial hypoperfusion/reperfusion tolerance with exercise training in hypertension. J Appl Physiol 2006;100:541–7. [4] Kemi OJ, Ellingsen O, Cevi M, Grimaldi S, Smith GL, Condorelli G, et al. Aerobic interval training enhances cardiomyocyte contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban. J Mol Cell Cardiol 2007;43:354–61. [5] Sánchez G, Escobar M, Pedrozo Z, Macho P, Domenech R, Härtel S, et al. Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection. Cardiovasc Res 2008;77:380–6. [6] Frasier CR, Sloan RC, Bostian PA, Gonzon MD, Kurowicki J, Lopresto SJ, et al. Short-term exercise preserves myocardial glutathione and decreases arrhythmias after thiol oxidation and ischemia in isolated rat hearts. J Appl Physiol 2011;111: 1751–9. [7] Zingman LV, Zhu Z, Sierra A, Stepniak E, Burnett CM, Maksymov G, et al. Exerciseinduced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation. J Mol Cell Cardiol 2011;51:72–81. [8] Dorn II GW. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 2007;49:962–70. [9] McMullen JR, Kennings GL. Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 2007;34:255–62. [10] Biffi A, Maron BJ, Di Giacinto B, Porcacchia P, Verdile L, Fernando F, et al. Relation between training-induced left ventricular hypertrophy and risk for ventricular tachyarrhythmias in elite athletes. Am J Cardiol 2008;101:1792–5. [11] Yang KC, Foeger NG, Marionneau C, Jay PY, McMullen JR, Nerbonne JM. Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy. J Physiol 2010;588:5015–32. [12] Benito B, Gay-Jordi G, Serrano-Mollar A, Guasch E, Shi Y, Tardif JC, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011;123:13–22. [13] Carneiro-Júnior MA, Quintão-Júnior JF, Drummond LR, Lavorato VN, Drummond FR, Amadeu MA, et al. The benefits of endurance training in cardiomyocyte function in hypertensive rats are reversed within four weeks of detraining. J Mol Cell Cardiol 2013;57:119–28. [14] Grisk O. Sympatho-renal interactions in the determination of arterial pressure: role in hypertension. Exp Physiol 2005;90:183–7. [15] Garciarena CD, Pinilla OA, Nally MB, Laquens RP, Escudero EM, Cingolani HE, et al. Endurance training in the spontaneously hypertensive rat: conversion of pathological into physiological cardiac hypertrophy. Hypertension 2009;53:708–14. [16] Libonati JR, Sabri A, Xiao C, MacDonnell SM, Renna BF. Exercise training improves systolic function in hypertensive myocardium. J Appl Physiol 2011;111:1637–43. [17] van Deel ED, de Boer M, Kuster SW, Boontje NM, Holemans P, Sipido KR, et al. Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis. J Mol Cell Cardiol 2011;50:1017–25. [18] Bassani JWM, Bassani RA, Bers DM. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol 1994;47:279–93. [19] Prímola-Gomes TN, Campos LA, Lauton-Santos S, Bathazar CH, Guatimosim S, Capettini LS, et al. Exercise capacity is related to calcium transients in ventricular cardiomyocytes. J Appl Physiol 2009;107:593–8. [20] Bassani JWM, Yuan W, Bers DM. Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol 1995;268:C1313–9. [21] Shannon TR, Ginsburg KS, Bers DM. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intrasarcoplasmic reticulum calcium concentration. Biophys J 2000;78:334–43. [22] Carvalho BMR, Bassani RA, Franchini KG, Bassani JWM. Enhanced calcium mobilization in rat ventricular myocytes during the onset of pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 2006;291:H1803–13. [23] Gómez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 1997;276:800–6. [24] McCall E, Ginsburg KS, Bassani RA, Shannon TR, Qi M, Samarel AM, et al. Ca flux, contractility, and excitation–contraction coupling in hypertrophic rat ventricular myocytes. Am J Physiol 1998;274:H1348–70. [25] Toischer K, Kögler H, Tenderich G, Grebe C, Seidler T, Van PN, et al. Elevated afterload, neuroendocrine stimulation, and human heart failure increase BPN levels and inhibit preload-dependent SERCA upregulation. Circ Heart Fail 2008;1:265–71. [26] Toischer K, Teucher N, Unsöld B, Kuhn M, Kögler H, Hasenfuss G. BPN controls early load-dependent regulation of SERCA through calcineurin. Basic Res Cardiol 2010;105:795–804. [27] Prosser BL, Khairallah RJ, Ziman AP, Ward CW, Lederer WJ. X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca2+]i. J Mol Cell Cardiol 2013;58:172–81. [28] Mokelke EA, Palmer BM, Cheung JY, Moore RL. Endurance training does not affect intrinsic calcium current characteristics in rat myocardium. Am J Physiol 1997;273:H1193–7. [29] Wang S, Ma JZ, Zhu SS, Xu DJ, Zou JG, Cao KJ. Swimming training can affect intrinsic calcium current characteristics in rat myocardium. Eur J Appl Physiol 2008;104:549–55.
Editorial
José W.M. Bassani⁎ Rosana A. Bassani Centro de Engenharia Biomédica and Dept. of Engenharia Biomédica/FEEC, Universidade Estadual de Campinas, Campinas SP, Brazil ⁎Corresponding author at: Centro de Engenharia Biomédica/UNICAMP, R. Alexander Fleming 163, 13083-881 Campinas, SP, Brazil. Tel.: +55 19 3521 9274; fax: +55 19 32893346. E-mail address: [email protected] (J.W.M. Bassani). 31 January 2013
49
Contents lists available at SciVerse ScienceDirect
Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Editorial
Working out the heart: Functional remodeling by endurance exercise training
Physical training, particularly in the case of aerobic exercise, has been shown to produce several physiological changes, among which are increase in the maximal oxygen uptake and general physical fitness, improvement in the sensitivity of some visceral reflexes, and decrease in the sympathetic drive to the heart, accompanied by increase in the vagal tone (e.g., [1,2]). The reported effects of exercise on the heart in the absence of cardiovascular affections include enhancement of contractility, acceleration of Ca 2+ transient and/or contraction kinetics, reduction of the oxygen requirements at increasing workloads, ischemic protection, and induction of anti-oxidant enzymes and chaperones [2–7]. Depending on the exercise modality, intensity and duration, myocardial hypertrophy may ensue. However, this so-called physiological hypertrophy differs from the hypertrophic growth that usually develops in response to chronic arterial hypertension and myocardial infarction. The latter is usually accompanied by increased expression of cell stress biomarkers (e.g., atrial natriuretic peptide), fibrosis, relative capillary rarefaction and greater propensity to arrhythmias, which are not observed in the physiological type of hypertrophy [8–11]. Thus, although hypertrophic growth is an adaptive response of the heart to increased hemodynamic load, physiological hypertrophy and pathological hypertrophy are quite distinct regarding the signaling pathway, morphological pattern, molecular and functional alterations, and evolution, as compensated pathological hypertrophy may progress to heart failure [2,8,9]. Nevertheless, it should be noticed that cardiac dysfunction and some phenotypic changes commonly observed in pathological hypertrophy can be induced by very intense and/or prolonged physical activity [12]. Would these 2 types of cardiac remodeling be superimposable? In the current issue of Journal of Molecular and Cellular Cardiology, Carneiro-Júnior et al., in their article The benefits of endurance training in cardiomyocyte function in hypertensive rats are reversed within four weeks of detraining [13], contribute to shed light on this issue reporting the molecular and functional effects of low-intensity endurance training (running) on the heart of spontaneously hypertensive rats, in which development of hypertension is associated with heightened sympathetic activity [14]. In their study, the authors observed that training, although not effective at normalizing the blood pressure, was able to reverse the myocardial overexpression of stress markers, one of the hallmarks of the pathologically hypertrophied heart. Their results are in agreement with previous data that indicate that different modalities of endurance training can lead to morphological, molecular and functional conversion of the pathological to the physiological hypertrophy phenotype in this hypertension model [15,16]. It should be pointed out, however, that this has not always been the case: failure of chronic exercise at improving cardiac function and producing beneficial effects was reported for 0022-2828/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.yjmcc.2013.02.017
compensated and decompensated hypertrophy induced by aortic constriction [17]. Carneiro-Júnior et al. [13] also described increased amplitude and acceleration of the timecourse of electrically-evoked Ca 2+ transients and contractions in myocytes from trained normotensive and hypertensive animals. These changes, which were correlated with heightened exercise capacity, are reported both in the absence or in the presence of cardiovascular affections [2,4]. While the increase in contraction amplitude could be partially explained by enhanced myofilament sensitivity to Ca 2+ after training [2], changes in cell Ca 2+ handling might significantly contribute to the improvement of the contractile activity. Most authors have observed that long-term exercise training increases the ventricular expression of the sarcoplasmic reticulum (SR) Ca 2+-ATPase (SERCA) and/or the ratio of SERCA and phospholamban, its endogenous negative regulator [2,4,13,15]. Such alterations should result in increased SERCA activity, which could explain the concurrently observed faster decline of Ca 2+ transients, as SERCA is the main pathway for removal of cytosolic Ca 2+ in mammalian myocardium [18]. From the physiological point of view, upregulation of SERCA expression and activity should permit adequate ventricular filling at higher heart rates, which are reached during exercise, thus allowing that cardiac output be compatible with the greater metabolic requirement of the tissues. This is possibly the reason why the rate of decline of the Ca2+ transients and SERCA protein levels have shown correlation with exercise capacity [13,19]. Additionally, augmented SERCA activity may result in increase in the SR Ca2+ content. This change might greatly impact the amount of Ca2+ released from the organelle and made available for the myofilaments, mostly because the fraction of the SR Ca2+ content that is released at systole (fractional SR Ca2+ release) is determined, in a positive and non-linear fashion, by the amount of Ca2+ stored in the SR [20,21]. Although the excitation–contraction coupling efficiency has not been examined by Carneiro-Júnior et. al. [13], such a mechanism might explain the greater Ca2+ transients observed by them and other authors, considering that the SR is the source of most of the Ca2+ that activates contraction. It still remains to be established whether exercise training and its associated increase in myocardial SERCA expression lead to greater SR Ca2+ loading and fractional release. In the case of hypertension models, the amount of released Ca 2+ or the fractional release was found to be enhanced during the early phases of compensated hypertrophy [22], whereas it tends to decrease in the chronic state and progression to heart failure [23,24]. In this respect, it is noteworthy that, under unphysiological conditions (e.g., arterial hypertension, myocardial infarction), SERCA activity and expression are usually decreased [25], in contrast to its consistent enhancement reported after exercise training. This divergence in the two kinds of hypertrophic remodeling might be at least
48
Editorial
partially dependent on the hemodynamic and neurohumoral conditions in each situation. Increase in the mechanical load was shown to result in acute myocardial SERCA upregulation. However, increased afterload and/or prolonged β-adrenergic stimulation (which is expected to occur in chronic hypertension, for instance) also increases the cardiac expression of brain natriuretic peptide (BNP). Evidence indicates that BNP upregulation, which occurs after aortic constriction and in the failing myocardium, seems to be implicated in the suppression of load-induced SERCA upregulation [25,26]. Thus, it is possible that the reversal of the overexpression of natriuretic peptides by chronic exercise, as reported by Carneiro-Júnior et al. [13] and others, may play a role in the SERCA upregulation observed in the hearts of trained animals. Because training did not diminish the blood pressure in hypertensive rats, it is possible that the decrease in basal sympathetic tone or the increase in venous return during the exercise sessions might be related to the augmented SERCA expression. The increase in end-diastolic ventricular volume during exercise might also be linked to redox RyR regulation in response to stretch [27]. Ca 2 + influx also is a key factor in excitation–contraction coupling. Even for unchanged SR Ca 2+ load, the fractional SR Ca 2+ release can be enhanced by increase in the trigger of the release process, namely, the L-type Ca 2+ current [20]. How exercise affects this trigger is a controversial issue and requires better clarification, as either increase, decrease or no change in the peak density of this current has been reported after aerobic exercise training [11,28,29]. Another potential mechanism affecting excitation–contraction coupling is the direct regulation of the SR Ca 2+ release channel (or ryanodine receptor, RyR). Little information is available on the effects of physical activity on RyR function and regulation. Sánchez et al. [5] described exercise-induced increase in myocardial NADPH oxidase activity, RyR S-glutathionylation and in the rate of Ca 2+-induced Ca 2+ release after exercise, which suggests involvement of RyR regulation by reactive oxygen species. This mechanism might mediate stretch-dependent regulation of SR Ca 2+ release [27]. While available evidence points out that exercise training can lead to myocardial remodeling associated with stimulation of Ca 2+ cycling, and enhanced contractility and exercise capacity, it also indicates that this remodeling depends on the persistence of its inductor, namely, the regular physical activity. Two weeks detraining are sufficient for attenuation of the ventricular hypertrophy, the enhanced aerobic capacity, and the changes in Ca 2+ transients and contraction brought about by long-term (8–13 weeks) endurance training. After 4 weeks of exercise cessation, such changes are no longer apparent [2,13]. These observations indicate the remarkable plasticity of myocardial regulation and the reversible nature of this type of remodeling of the myocardium, which requires continuous recruitment of regulatory mechanisms for its maintenance. The growing knowledge on the cardiac effects of exercise has revealed important aspects of the dynamic and complex nature of the regulation of the myocardium, at molecular and functional levels. At the same time, it has pointed out the clinical relevance and potential of regular, moderate physical activity as a valuable non-pharmacological alternative for prevention of cardiovascular dysfunctions, as well as for improvement of cardiac performance of the diseased myocardium. Disclosures None. Funding This work was funded by grant of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—302996/2011-7 to JWMB).
References [1] De Angelis K, Wichi RB, Jesus WR, Moreira ED, Morris K, Krieger EM, et al. Exercise training changes autonomic cardiovascular balance in mice. J Appl Physiol 2004;96:2174–8. [2] Kemi OJ, Wisløff U. Mechanisms of exercise-induced improvements in the contractile apparatus of the mammalian myocardium. Acta Physiol (Oxf) 2010;199: 425–39. [3] Reger PO, Barbe MF, Amin M, Renna BF, Hewston LA, MacDonnell SM, et al. Myocardial hypoperfusion/reperfusion tolerance with exercise training in hypertension. J Appl Physiol 2006;100:541–7. [4] Kemi OJ, Ellingsen O, Cevi M, Grimaldi S, Smith GL, Condorelli G, et al. Aerobic interval training enhances cardiomyocyte contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban. J Mol Cell Cardiol 2007;43:354–61. [5] Sánchez G, Escobar M, Pedrozo Z, Macho P, Domenech R, Härtel S, et al. Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection. Cardiovasc Res 2008;77:380–6. [6] Frasier CR, Sloan RC, Bostian PA, Gonzon MD, Kurowicki J, Lopresto SJ, et al. Short-term exercise preserves myocardial glutathione and decreases arrhythmias after thiol oxidation and ischemia in isolated rat hearts. J Appl Physiol 2011;111: 1751–9. [7] Zingman LV, Zhu Z, Sierra A, Stepniak E, Burnett CM, Maksymov G, et al. Exerciseinduced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation. J Mol Cell Cardiol 2011;51:72–81. [8] Dorn II GW. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 2007;49:962–70. [9] McMullen JR, Kennings GL. Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 2007;34:255–62. [10] Biffi A, Maron BJ, Di Giacinto B, Porcacchia P, Verdile L, Fernando F, et al. Relation between training-induced left ventricular hypertrophy and risk for ventricular tachyarrhythmias in elite athletes. Am J Cardiol 2008;101:1792–5. [11] Yang KC, Foeger NG, Marionneau C, Jay PY, McMullen JR, Nerbonne JM. Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy. J Physiol 2010;588:5015–32. [12] Benito B, Gay-Jordi G, Serrano-Mollar A, Guasch E, Shi Y, Tardif JC, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011;123:13–22. [13] Carneiro-Júnior MA, Quintão-Júnior JF, Drummond LR, Lavorato VN, Drummond FR, Amadeu MA, et al. The benefits of endurance training in cardiomyocyte function in hypertensive rats are reversed within four weeks of detraining. J Mol Cell Cardiol 2013;57:119–28. [14] Grisk O. Sympatho-renal interactions in the determination of arterial pressure: role in hypertension. Exp Physiol 2005;90:183–7. [15] Garciarena CD, Pinilla OA, Nally MB, Laquens RP, Escudero EM, Cingolani HE, et al. Endurance training in the spontaneously hypertensive rat: conversion of pathological into physiological cardiac hypertrophy. Hypertension 2009;53:708–14. [16] Libonati JR, Sabri A, Xiao C, MacDonnell SM, Renna BF. Exercise training improves systolic function in hypertensive myocardium. J Appl Physiol 2011;111:1637–43. [17] van Deel ED, de Boer M, Kuster SW, Boontje NM, Holemans P, Sipido KR, et al. Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis. J Mol Cell Cardiol 2011;50:1017–25. [18] Bassani JWM, Bassani RA, Bers DM. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol 1994;47:279–93. [19] Prímola-Gomes TN, Campos LA, Lauton-Santos S, Bathazar CH, Guatimosim S, Capettini LS, et al. Exercise capacity is related to calcium transients in ventricular cardiomyocytes. J Appl Physiol 2009;107:593–8. [20] Bassani JWM, Yuan W, Bers DM. Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol 1995;268:C1313–9. [21] Shannon TR, Ginsburg KS, Bers DM. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intrasarcoplasmic reticulum calcium concentration. Biophys J 2000;78:334–43. [22] Carvalho BMR, Bassani RA, Franchini KG, Bassani JWM. Enhanced calcium mobilization in rat ventricular myocytes during the onset of pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 2006;291:H1803–13. [23] Gómez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 1997;276:800–6. [24] McCall E, Ginsburg KS, Bassani RA, Shannon TR, Qi M, Samarel AM, et al. Ca flux, contractility, and excitation–contraction coupling in hypertrophic rat ventricular myocytes. Am J Physiol 1998;274:H1348–70. [25] Toischer K, Kögler H, Tenderich G, Grebe C, Seidler T, Van PN, et al. Elevated afterload, neuroendocrine stimulation, and human heart failure increase BPN levels and inhibit preload-dependent SERCA upregulation. Circ Heart Fail 2008;1:265–71. [26] Toischer K, Teucher N, Unsöld B, Kuhn M, Kögler H, Hasenfuss G. BPN controls early load-dependent regulation of SERCA through calcineurin. Basic Res Cardiol 2010;105:795–804. [27] Prosser BL, Khairallah RJ, Ziman AP, Ward CW, Lederer WJ. X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca2+]i. J Mol Cell Cardiol 2013;58:172–81. [28] Mokelke EA, Palmer BM, Cheung JY, Moore RL. Endurance training does not affect intrinsic calcium current characteristics in rat myocardium. Am J Physiol 1997;273:H1193–7. [29] Wang S, Ma JZ, Zhu SS, Xu DJ, Zou JG, Cao KJ. Swimming training can affect intrinsic calcium current characteristics in rat myocardium. Eur J Appl Physiol 2008;104:549–55.
Editorial
José W.M. Bassani⁎ Rosana A. Bassani Centro de Engenharia Biomédica and Dept. of Engenharia Biomédica/FEEC, Universidade Estadual de Campinas, Campinas SP, Brazil ⁎Corresponding author at: Centro de Engenharia Biomédica/UNICAMP, R. Alexander Fleming 163, 13083-881 Campinas, SP, Brazil. Tel.: +55 19 3521 9274; fax: +55 19 32893346. E-mail address: [email protected] (J.W.M. Bassani). 31 January 2013
49