Published online before print February 16, 2009, doi: 10.1161/HYPERTENSIONAHA.108.126805
(Hypertension. 2009;53:708.)
© 2009 American Heart Association, Inc.
Original Articles |
Endurance Training in the Spontaneously Hypertensive Rat
Conversion of Pathological into Physiological Cardiac Hypertrophy
From the Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina.
Correspondence to Irene L. Ennis, Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, UNLP, 60 y 120 (1900) La Plata, Argentina. E-mail iennis{at}med.unlp.edu.ar
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The effect of endurance training (swimming 90 min/d for 5 days a week for 60 days) on cardiac hypertrophy was investigated in the spontaneously hypertensive rat (SHR). Sedentary SHRs (SHR-Cs) and normotensive Wistar rats were used as controls. Exercise training enhanced myocardial hypertrophy assessed by left ventricular weight/tibial length (228±7 versus 251±5 mg/cm in SHR-Cs and exercised SHRs [SHR-Es], respectively). Myocyte cross-sectional area increased
40%, collagen volume fraction decreased 50%, and capillary density increased 45% in SHR-Es compared with SHR-Cs. The mRNA abundance of atrial natriuretic factor and myosin light chain 2 was decreased by the swimming routine (100±19% versus 41±10% and 100±8% versus 61±9% for atrial natriuretic factor and myosin light chain 2 in SHR-Cs and SHR-Es, respectively). The expression of sarcoplasmic reticulum Ca2+ pump was significantly augmented, whereas that of Na+/Ca2+ exchanger was unchanged (93±7% versus 167±8% and 158±13% versus 157±7%, sarcoplasmic reticulum Ca2+ pump and Na+/Ca2+ exchanger in SHR-Cs and SHR-Es, respectively; P<0.05). Endurance training inhibited apoptosis, as reflected by a decrease in caspase 3 activation and poly(ADP-ribose) polymerase-1 cleavage, and normalized calcineurin activity without inducing significant changes in the phosphatidylinositol 3-kinase/Akt pathway. The swimming routine improved midventricular shortening determined by echocardiography (32.4±0.9% versus 36.9±1.1% in SHR-Cs and SHR-Es, respectively; P<0.05) and decreased the left ventricular free wall thickness/left ventricular cavity radius toward an eccentric model of cardiac hypertrophy (0.59±0.02 versus 0.53±0.01 in SHR-Cs and SHR-Es, respectively; P<0.05). In conclusion, we present data demonstrating the effectiveness of endurance training to convert pathological into physiological hypertrophy improving cardiac performance. The reduction of myocardial fibrosis and calcineurin activity plus the increase in capillary density represent factors to be considered in determining this beneficial effect.
Key Words: exercise training • cardiac hypertrophy • hypertension • calcium handling • apoptosis • signaling pathways
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Before the late 1980s, patients with heart failure were advised to avoid physical exercise. However, it is well known that regular physical activity protects against cardiovascular disease. It is widely recognized that chronic exercise training attenuates several of the main risk factors for cardiovascular diseases, such as high blood pressure and insulin resistance.1,2 Interestingly, it has been reported that low-intensity exercise training markedly delayed the onset of decompensate heart failure and improved survival in the spontaneously hypertensive heart failure rat model.3 This effect was attained independent of any significant effect on blood pressure.3 Exercise training in selected heart failure patients has been demonstrated not only to be safe but also beneficial.4,5
Diverse stimuli, such us hypertension and myocardial infarction, induce the development of cardiac hypertrophy (CH) that constitutes one of the main cardiovascular risk factors and a poor prognostic sign associated with nearly all forms of heart failure.6 This type of CH is known as pathological. However, cardiac enlargement may represent a favorable adaptation restricted to match the increase in functional demand in response to exercise training, with preserved or enhanced cardiac function, that does not cause or contribute to disease.7,8 This type of CH is known as physiological hypertrophy (ie, athlete’s heart).
The purpose of this study was to assess the effects of chronic physical training (swimming routine) on pathological CH induced by pressure overload in the animal model of the spontaneously hypertensive rat (SHR). The results presented here support that exercise training converts the pattern of pathological into physiological hypertrophy, improving myocardial performance.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Male SHRs at 4 months of age were randomly assigned to sedentary (SHR-C; n=13) and swimming-trained (SHR-E; n=9) groups. Age- and sex-matched normotensive Wistar rats (n=5) were used as nonhypertrophied controls. The study was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the 60-day experimental protocol was approved by the La Plata School of Medicine Animal Welfare Committee.
For detailed Materials and Methods, please see the online data supplement, available at http://hyper.ahajournals.org.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Left ventricular (LV) structural, molecular, and functional remodeling was studied at 60 days of exercise training in SHRs in the compensated stage of CH. Age- and sex-matched sedentary SHRs, as well as normotensive rats (Wistar), were use as hypertrophic and normotrophic controls, respectively.
Cardiac Gross Morphology, Histology, and Gene Expression
Morphological data from each experimental group are summarized in the Table. Exercise training exacerbated CH in SHRs, as revealed by the increase in the left ventricular mass/tibial length ratio and the LV mass index. No significant changes were detected in systolic blood pressure or body weight compared with the sedentary SHR. A significant increase in LV diastolic diameter was detected in the SHR-E at the end of the 60-day swimming protocol. The geometry of the LV chamber was modified by the exercise routine from a concentric toward an eccentric type of CH, as revealed by the decrease in the relation between the thickness of the LV free wall and the radius of the cavity.
|
Exercise training induced an average increase of 40% in mean cardiac myocyte cross-sectional area, whereas collagen volume fraction was decreased by 50%, making its abundance not different to that of normotensive rats (Figure 1A and 1B). Interestingly, these histological changes in the myocardium of the exercised rats were accompanied by a significant increase in capillary density (Figure 1C). Myocardial capillary density showed a tendency toward a smaller value in the SHR-Cs compared with the nonhypertrophied myocardium of the Wistar rats, although it did not reach statistical significance.
|
P<0.05 vs Wistar, by ANOVA. MLC-2 indicates myosin light chain 2.Because it is well known that pathological CH is characterized by the induction of genes normally expressed during fetal development, such as atrial natriuretic factor (ANF) and myosin light chain 2, the mRNA abundance of these 2 genes was assessed in the myocardium of sedentary and exercised SHRs by real-time RT-PCR. Swimming training significantly lowered the myocardial expression of both ANF and myosin light chain 2 (Figure 1D). The SERCA2a and the Na+/Ca2+ exchanger are 2 proteins involved in calcium cycling in which expression has been reported to be altered (downregulation of SERCA and upregulation of Na+/Ca2+ exchanger) in several models of experimental and human pathological CH and cardiac failure.9 Physical training induced a significant increase in the expression of SERCA2a, whereas no changes were detected in the expression of Na+/Ca2+ exchanger (Figure 2A and 2B).
|
Exercise Training Downregulates Calcineurin Activity
Periodic swimming significantly decreased calcineurin A (CnA) β expression, a good indicator of calcineurin activity,10,11 in the hypertrophied myocardium of the SHR-E to levels not different from those detected in the myocardium of normotensive rats (Figure 3A). On the other hand, no effect of endurance training was evident on the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway (Figure 3B and 3C).
|
(B) and phospho-Akt (P-Akt; C) was significantly higher in the hypertrophied myocardium of the SHR-C compared with the normotensive rats and remained unchanged at the end of the swimming protocol. Average data are depicted in the bar graphs, and representative blots are shown on top of the bars for each panel figure. *P<0.05 vs SHR-C, by ANOVA; n=5 for each group.
Apoptosis Is Inhibited by Exercise Training
Because apoptosis is increased in hypertensive CH and it has been demonstrated to play a role in the transition from hypertrophy to heart failure,12–15 we aimed to determine whether exercise training was able to induce an inhibitory effect on the apoptosis cascade. To this purpose, we assessed by protein immunoblotting the activation of procaspase-3, as well as the cleavage extent of poly(ADP-ribose) polymerase by caspase-3 in the myocardium of exercised and sedentary SHRs and in that of normotensive rats. Endurance training significantly decreased the extent of procaspase-3 cleaved into fragments of 17 kDa (Figure 4A), as well as the amount of fragments of 85 kDa from the precursor poly(ADP-ribose) polymerase-1 (Figure 4B), although not to the levels detected in normotensive rats, indicating a decreased activation of both effectors of the apoptotic pathway.
|
Endurance Training Improves Cardiac Function
At the beginning of the experimental protocol, no difference was observed between the experimental groups with respect to LV systolic function evaluated echocardiographically. However, a slight but significant increase in midventricular shortening was detected in the trained SHR at the completion of the 60-day swimming routine (Figure 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In this study, we analyzed the myocardial effects of endurance training (periodic swimming) in an experimental model of pathological CH induced by pressure overload. Our results demonstrate that periodic exercise training is capable of transforming hypertension-induced pathological CH into physiological CH at the structural, molecular, and functional levels, at least when initiated in the compensated phase of CH. These data are in agreement with recent studies supporting the idea that low-intensity exercise training may result in beneficial adaptations, even in the presence of heart failure.3,16 However, excessive exercise can have deleterious effects on cardiac remodeling and function, as reported by Schultz et al.17
It is widely recognized that exercise training protects individuals from a variety of cardiovascular diseases.3,16,18,19 However, the mechanisms underlying this beneficial effect are not completely understood. It is interesting to note that, in our experimental protocol, endurance training exerted its beneficial effect without modifying systolic blood pressure, a result that is in agreement with previous reports.20,21
The cardiac response elicited by pressure overload differs greatly at the structural and functional levels from that induced by endurance training. Pathological CH is characterized by cardiac fibrosis; decrease vascularization; enhanced apoptosis; re-expression of fetal genes; downregulation of metabolic genes, especially those involved in fatty acid metabolism; LV dysfunction; and increase mortality (for review, see References 22–24. Both physiological and pathological CHs are associated with alterations in cardiac geometry; pressure overload usually determines concentric hypertrophy (increased wall thickness with relatively small cavities), whereas volume-overloaded hearts present eccentric hypertrophy (proportional increase in wall thickness and chamber dimensions). The latter is the pattern seen with endurance exercise training, such as long distance running or swimming.8 Despite the fact that these differences between physiological and pathological CHs were well known, until relatively recently, it was unclear whether these 2 forms of hypertrophy were induced by different intracellular signaling cascades. Because usually the stimuli for pathological CH are chronic, whereas those for physiological CH are intermittent, the duration of the stimulus was thought to be critical in determining the phenotypic response. However, Perrino et al25 demonstrated in an interesting murine model of intermittent pressure overload that it was the nature of the triggering stimulus and the intracellular signaling pathway activated, as opposed to the duration, that established the type of CH. At present, 
2 cascades playing distinct roles in physiological and pathological CHs have been characterized, the PI3-K/Akt and the calcineurin pathways, respectively (reviewed in References 23,24). We demonstrated that endurance training was able to normalize calcineurin activity without interfering with the PI3-K/Akt pathway. This result is of great importance, because calcineurin appears to largely mediate pathological but not physiological CH.10,11,26–31 Calcineurin is a calcium/calmodulin-dependent serine/threonine phosphatase that dephosphorylates members of the nuclear factor of activated T cells transcription factor family permitting their nuclear translocation and activation of transcription. Transgenic mice overexpressing an activated form of calcineurin or NFAT3 in the myocardium developed CH that rapidly progressed to heart failure.28 On the contrary, CnAβ-deficient mice displayed an impaired hypertrophic response to pathological stimuli, such us pressure overload and angiotensin II or isoproterenol infusion.26 Furthermore, in NFAT-luciferase reporter transgenic mice subjected either to physiological (exercise training or growth hormone-IGF1 infusion) or to pathological (pressure overload or myocardial infarction) stimuli, calcineurin/NFAT activity was upregulated only in the pathological models.29
The PI3-K/Akt signaling pathway is one of the main signaling cascades involved in normal postnatal cardiac growth.32 Its upregulation has been demonstrated to induce both physiological and pathological CHs.32–34 The phenotype determined may be related, at least in part, to the degree of Akt upregulation; overstimulation of this pathway would lead to pathological CH.35 On the other hand, it is relevant that the PI3-K/Akt pathway promotes cell survival by inhibiting apoptosis at multiple points.36 This makes the strategy of endurance training even more interesting as a therapeutic tool to induce pathological CH regression, because it does not interfere with the PI3-K/Akt pathway, whereas it downregulates the pathological cascade of calcineurin/NFAT.
Increased circulating levels of ANF have been positively correlated with the severity of heart failure.37,38 Importantly, our swimming protocol reduced the expression of ANF, at least at the mRNA level, as indicated by the real-time RT-PCR experiments, supporting the idea that endurance training impacts beneficially on cardiac performance, even in the presence of pathological CH.
Relatively few studies in experimental models of heart failure have addressed the effect of exercise training on the myocardial expression of calcium-handling proteins with considerable variability with respect to their findings.3,39–42 However, we are not aware of this kind of study in any model of pathological CH. In our experimental setting we detected an upregulation of the expression of SERCA2a induced by the swimming routine. Although we do not have direct evidence supporting a cause-effect relationship between SERCA2a upregulation and cardiac function, we think that it is likely involved in the enhancement in cardiac function detected by echocardiography. Moreover, our data are in agreement with previous reports demonstrating that the improvement in intracellular Ca2+ regulation underlies the benefits of exercise training on ventricular function in heart failure.41,42 We chose to measure fractional shortening at the LV midwall level because it has been shown to be an accurate and convenient index of LV systolic function superior to endocardial fractional shortening in hypertensive humans and animals.43,44,45 Another factor that is probably contributing to the better contractility detected in the trained SHR is the downregulation of calcineurin activity induced by exercise training, because it has been reported that this phosphatase exerts negative inotropic effect.31,46,47 The normalization of interstitial fibrosis, the increase in capillary density, and the decreased activity of the apoptosis cascade in the SHR-E may be also involved in the improvement in cardiac function evidenced in the echocardiographic study. Interestingly, in a transgenic mice model of CH due to cardiac-specific inducible Akt1 expression, it was demonstrated that the imbalance between myocyte growth and coronary angiogenesis plays a critical role in the contractile dysfunction.48 This finding led the authors to propose that it may be advantageous to stimulate angiogenesis as part of a general strategy to prevent or reverse heart failure. In our experimental conditions, exercise training did increase myocardial capillary density in the SHR.
Perspectives
In the present work we provide new insights into the molecular mechanisms underlying the beneficial effects of endurance training in pathological CH. We demonstrate in an animal model of hypertension-induced pathological CH that exercise training decreases myocardial interstitial collagen abundance, increases myocardial capillary density, and upregulates SERCA2a expression improving LV systolic function. We speculate that these beneficial changes were, at least in part, related to the downregulation of calcineurin activity, because this signaling pathway has been demonstrated to underlie the development of pathological and not physiological CH, although with some controversial results.23,29 Figure 6 schematically summarizes the results described above.
|
In this scenario, our results lend support to the idea that endurance training can positively transform pathological into physiological CH. This finding could have clinical relevance in the design of therapeutic strategies for the prevention of heart failure as the consequence of hypertension-induced CH progression.
|
Acknowledgments |
|---|
Sources of Funding
H.E.C. and I.L.E. are established investigators of Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. C.D.G. is a fellow of Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. This study was supported by grants PICT 05-14565 (to I.L.E.) and PICT 05-38057 (to H.E.C.) from Agencia Nacional de Promoción Científica y Tecnológica, Argentina, and PIP 5141 (to H.E.C.) from Consejo Nacional de Ciencia y Técnica, Argentina.
Disclosures
None.
Received November 20, 2008; first decision December 11, 2008; accepted January 27, 2009.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Cox KL, Puddey IB, Morton AR, Burke V, Beilin LJ, McAleer M. Exercise and weight control in sedentary overweight men: effects on clinic and ambulatory blood pressure. J Hypertens. 1996; 14: 779–790.[CrossRef][Medline] [Order article via Infotrieve]
2. Rogers MW, Probst MM, Gruber JJ, Berger R, Boone JB Jr. Differential effects of exercise training intensity on blood pressure and cardiovascular responses to stress in borderline hypertensive humans. J Hypertens. 1996; 14: 1369–1375.[CrossRef][Medline] [Order article via Infotrieve]
3. Emter CA, McCune SA, Sparagna GC, Radin MJ, Moore RL. Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats. Am J Physiol Heart Circ Physiol. 2005; 289: H2030–H2038.
4. Wisloff U, Stoylen A, Loennechen JP, Bruvold M, Rognmo O, Haram PM, Tjonna AE, Helgerud J, Slordahl SA, Lee SJ, Videm V, Bye A, Smith GL, Najjar SM, Ellingsen O, Skjaerpe T. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation. 2007; 115: 3086–3094.
5. Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, Schoene N, Schuler G. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: a randomized trial. JAMA. 2000; 283: 3095–3101.
6. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561–1566.[Abstract]
7. Fagard RH. Impact of different sports and training on cardiac structure and function. Cardiol Clin. 1997; 15: 397–412.[CrossRef][Medline] [Order article via Infotrieve]
8. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete’s heart. A meta-analysis of cardiac structure and function. Circulation. 2000; 101: 336–344.
9. Inesi G, Prasad AM, Pilankatta R. The Ca2+ ATPase of cardiac sarcoplasmic reticulum: physiological role and relevance to diseases. Biochem Biophys Res Commun. 2008; 369: 182–187.[CrossRef][Medline] [Order article via Infotrieve]
10. Haq S, Choukroun G, Lim H, Tymitz KM, del Monte F, Gwathmey J, Grazette L, Michael A, Hajjar R, Force T, Molkentin JD. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation. 2001; 103: 670–677.
11. Taigen T, De Windt LJ, Lim HW, Molkentin JD. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2000; 97: 1196–1201.
12. Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA, Pardo J. Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats. Hypertension. 1997; 30: 1029–1034.
13. Fortuno MA, Ravassa S, Etayo JC, Diez J. Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats: effects of AT1 blockade with losartan. Hypertension. 1998; 32: 280–286.
14. Hamet P, Richard L, Dam TV, Teiger E, Orlov SN, Gaboury L, Gossard F, Tremblay J. Apoptosis in target organs of hypertension. Hypertension. 1995; 26: 642–648.
15. Li Z, Bing OH, Long X, Robinson KG, Lakatta EG. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol. 1997; 272: H2313–H2319.[Medline] [Order article via Infotrieve]
16. Konhilas JP, Watson PA, Maass A, Boucek DM, Horn T, Stauffer BL, Luckey SW, Rosenberg P, Leinwand LA. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ Res. 2006; 98: 540–548.
17. Schultz RL, Swallow JG, Waters RP, Kuzman JA, Redetzke RA, Said S, de Escobar GM, Gerdes AM. Effects of excessive long-term exercise on cardiac function and myocyte remodeling in hypertensive heart failure rats. Hypertension. 2007; 50: 410–416.
18. Fang J, Wylie-Rosett J, Cohen HW, Kaplan RC, Alderman MH. Exercise, body mass index, caloric intake, and cardiovascular mortality. Am J Prev Med. 2003; 25: 283–289.[CrossRef][Medline] [Order article via Infotrieve]
19. Kannel WB, Wilson P, Blair SN. Epidemiological assessment of the role of physical activity and fitness in development of cardiovascular disease. Am Heart J. 1985; 109: 876–885.[CrossRef][Medline] [Order article via Infotrieve]
20. Filho AG, Ferreira AJ, Santos SH, Neves SR, Silva Camargos ER, Becker LK, Belchior HA, Dias-Peixoto MF, Pinheiro SV, Santos RA. Selective increase of angiotensin(1–7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training. Exp Physiol. 2008; 93: 589–598.
21. Medeiros A, Oliveira EM, Gianolla R, Casarini DE, Negrao CE, Brum PC. Swimming training increases cardiac vagal activity and induces cardiac hypertrophy in rats. Braz J Med Biol Res. 2004; 37: 1909–1917.[Medline] [Order article via Infotrieve]
22. Dorn GW II. The fuzzy logic of physiological cardiac hypertrophy. Hypertension. 2007; 49: 962–970.
23. McMullen JR, Jennings GL. Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol. 2007; 34: 255–262.[Medline] [Order article via Infotrieve]
24. Selvetella G, Hirsch E, Notte A, Tarone G, Lembo G. Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence. Cardiovasc Res. 2004; 63: 373–380.
25. Perrino C, Naga Prasad SV, Mao L, Noma T, Yan Z, Kim HS, Smithies O, Rockman HA. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest. 2006; 116: 1547–1560.[CrossRef][Medline] [Order article via Infotrieve]
26. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, Molkentin JD. Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice. Proc Natl Acad Sci U S A. 2002; 99: 4586–4591.
27. Nagata K, Somura F, Obata K, Odashima M, Izawa H, Ichihara S, Nagasaka T, Iwase M, Yamada Y, Nakashima N, Yokota M. AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats. Hypertension. 2002; 40: 168–174.
28. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93: 215–228.[CrossRef][Medline] [Order article via Infotrieve]
29. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res. 2004; 94: 110–118.
30. Zou Y, Yamazaki T, Nakagawa K, Yamada H, Iriguchi N, Toko H, Takano H, Akazawa H, Nagai R, Komuro I. Continuous blockade of L-type Ca2+ channels suppresses activation of calcineurin and development of cardiac hypertrophy in spontaneously hypertensive rats. Hypertens Res. 2002; 25: 117–124.[CrossRef][Medline] [Order article via Infotrieve]
31. Ennis IL, Garciarena CD, Escudero EM, Perez NG, Dulce RA, Camilion de Hurtado MC, Cingolani HE. Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na+/H+ exchanger-1 (NHE-1) inhibition. Can J Physiol Pharmacol. 2007; 85: 301–310.[CrossRef][Medline] [Order article via Infotrieve]
32. Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J, Rosenzweig A, Kahn CR, Abel ED, Walsh K. Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. J Biol Chem. 2002; 277: 37670–37677.
33. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem. 2002; 277: 22896–22901.
34. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A. 2002; 99: 12333–12338.
35. O'Neill BT, Abel ED. Akt1 in the cardiovascular system: friend or foe? J Clin Invest. 2005; 115: 2059–2064.[CrossRef][Medline] [Order article via Infotrieve]
36. Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle. 2003; 2: 220–223.[Medline] [Order article via Infotrieve]
37. Brandt RR, Wright RS, Redfield MM, Burnett JC Jr. Atrial natriuretic peptide in heart failure. J Am Coll Cardiol. 1993; 22: 86A–92A.[Medline] [Order article via Infotrieve]
38. Burnett JC Jr, Kao PC, Hu DC, Heser DW, Heublein D, Granger JP, Opgenorth TJ, Reeder GS. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science. 1986; 231: 1145–1147.
39. Lu L, Mei DF, Gu AG, Wang S, Lentzner B, Gutstein DE, Zwas D, Homma S, Yi GH, Wang J. Exercise training normalizes altered calcium-handling proteins during development of heart failure. J Appl Physiol. 2002; 92: 1524–1530.
40. Zhang XQ, Ng YC, Musch TI, Moore RL, Zelis R, Cheung JY. Sprint training attenuates myocyte hypertrophy and improves Ca2+ homeostasis in postinfarction myocytes. J Appl Physiol. 1998; 84: 544–552.
41. Medeiros A, Rolim NP, Oliveira RS, Rosa KT, Mattos KC, Casarini DE, Irigoyen MC, Krieger EM, Krieger JE, Negrao CE, Brum PC. Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice. J Appl Physiol. 2008; 104: 103–109.
42. Rolim NP, Medeiros A, Rosa KT, Mattos KC, Irigoyen MC, Krieger EM, Krieger JE, Negrao CE, Brum PC. Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure. Physiol Genomics. 2007; 29: 246–252.
43. Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy. Circulation. 1991; 83: 1676–1684.
44. Shimizu G, Hirota Y, Kawamura K. Empiric determination of the transition from concentric hypertrophy to congestive heart failure in essential hypertension. J Am Coll Cardiol. 1995; 25: 888–894.[Abstract]
45. Ono K, Masuyama T, Yamamoto K, Doi R, Sakata Y, Nishikawa N, Mano T, Kuzuya T, Takeda H, Hori M. Echo doppler assessment of left ventricular function in rats with hypertensive hypertrophy. J Am Soc Echocardiogr. 2002; 15: 109–117.[CrossRef][Medline] [Order article via Infotrieve]
46. Sah R, Oudit GY, Nguyen TT, Lim HW, Wickenden AD, Wilson GJ, Molkentin JD, Backx PH. Inhibition of calcineurin and sarcolemmal Ca2+ influx protects cardiac morphology and ventricular function in K(v)4.2N transgenic mice. Circulation. 2002; 105: 1850–1856.
47. Li J, Yatani A, Kim SJ, Takagi G, Irie K, Zhang Q, Karoor V, Hong C, Yang G, Sadoshima J, Depre C, Vatner DE, West MJ, Vatner SF. Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy. Cardiovasc Res. 2003; 59: 649–657.
48. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 2005; 115: 2108–2118.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  B.ņa Benito and S. Nattel Exercise training as a treatment for heart failure: potential mechanisms and clinical implications J. Physiol., November 1, 2009; 587(21): 5011 - 5013. [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Thornton and K. Hess Exercise Generates Lactate and Fluid Intake: Effects on Mitochondrial Function in Heart and Vascular Smooth Muscle Hypertension, August 1, 2009; 54(2): e14 - e14. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||