Protective effects of exercise and phosphoinositide 3-kinase(p110α) signaling in dilated and hypertrophic cardiomyopathy

Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110α isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exercise-induced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110α) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiac-specific transgenic mice with increased or decreased PI3K(p110α) activity to the DCM model, and subjected PI3K(p110α) transgenics to acute pressure overload (ascending aortic constriction). Life-span, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110α) activity prolonged survival in the DCM model by 15–20%. In contrast, reduced PI3K(p110α) activity drastically shortened lifespan by ≈50%. Increased PI3K(p110α) activity had a favorable effect on cardiac function and fibrosis in the pressure-overload model and attenuated pathological growth. PI3K(p110α) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110γ) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110α) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.

[1]  S. Cook,et al.  Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling , 2006, Circulation research.

[2]  Hyung-Suk Kim,et al.  Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. , 2006, The Journal of clinical investigation.

[3]  K. Okkenhaug,et al.  Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation , 2006, Nature.

[4]  M. Emdin,et al.  Aerobic training decreases B-type natriuretic peptide expression and adrenergic activation in patients with heart failure. , 2006, Journal of the American College of Cardiology.

[5]  William A Weiss,et al.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. , 2006, Cancer cell.

[6]  D. Warburton,et al.  Health benefits of physical activity: the evidence , 2006, Canadian Medical Association Journal.

[7]  L. Leinwand,et al.  Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy , 2006, Circulation research.

[8]  R. DePinho,et al.  Class IA Phosphoinositide 3-Kinase Regulates Heart Size and Physiological Cardiac Hypertrophy , 2005, Molecular and Cellular Biology.

[9]  G. Condorelli,et al.  Akt Mediates the Cross-Talk Between &bgr;-Adrenergic and Insulin Receptors in Neonatal Cardiomyocytes , 2005, Circulation research.

[10]  J. Rohn,et al.  Gene Targeting Attention to Detail , 2004, Cell.

[11]  L. Silengo,et al.  PI3Kγ Modulates the Cardiac Response to Chronic Pressure Overload by Distinct Kinase-Dependent and -Independent Effects , 2004, Cell.

[12]  R. Walsh.  Molecular Mechanisms of Cardiac Hypertrophy and Failure , 2004 .

[13]  Qing Nie,et al.  Mouse cardiac surgery: comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. , 2004, Physiological genomics.

[14]  P. Kang,et al.  The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway* , 2004, Journal of Biological Chemistry.

[15]  Jian Xu,et al.  Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy , 2004, Circulation research.

[16]  A. Cohen-Solal,et al.  Physical activity for primary and secondary prevention. Position paper of the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology , 2003, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[17]  P. Kang,et al.  Phosphoinositide 3-kinase(p110α) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  I. Fraser,et al.  Navigating the signalling network in mouse cardiac myocytes , 2002, Nature.

[19]  J. Molkentin,et al.  Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. , 2002, Circulation research.

[20]  P. Kang,et al.  Akt/Protein Kinase B Promotes Organ Growth in Transgenic Mice , 2002, Molecular and Cellular Biology.

[21]  A. Michelucci,et al.  Increased Cardiac Sympathetic Activity and Insulin-Like Growth Factor-I Formation Are Associated With Physiological Hypertrophy in Athletes , 2001, Circulation research.

[22]  P. Kang,et al.  The conserved phosphoinositide 3‐kinase pathway determines heart size in mice , 2000, The EMBO journal.

[23]  J. Christie,et al.  Serum levels of total and free IGF-I and IGFBP-3 are increased and maintained in long-term training. , 1999, Journal of applied physiology.

[24]  E. Woodcock,et al.  Acute effects of cell isolation on InsP profiles in adult rat cardiomyocytes. , 1997, Journal of molecular and cellular cardiology.

[25]  R. Fagard.  Impact of different sports and training on cardiac structure and function. , 1997, Cardiology clinics.

[26]  G. Jennings.  MECHANISMS FOR REDUCTION OF CARDIOVASCULAR RISK BY REGULAR EXERCISE , 1995, Clinical and Experimental Pharmacology and Physiology.

[27]  D. Levy,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.

[28]  B. Ip.  The role of physical activity in the prevention and treatment of noncommunicable diseases. , 1988 .

[29]  B. Nadal-Ginard,et al.  Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. , 1988, Proceedings of the National Academy of Sciences of the United States of America.