Cardiac Fibrosis Alleviated by Exercise Training Is AMPK-Dependent

Regular exercise can protect the heart against external stimuli, but the mechanism is not well understood. We determined the role of adenosine monophosphate-activated protein kinase (AMPK) in regulating swimming exercise-mediated cardiac protection against β-adrenergic receptor overstimulation with isoproterenol (ISO) in mice. Ten-week-old AMPKα2+/+ and AMPKα2-knockout (AMPKα2-/-) littermates were subjected to 4 weeks of swimming training (50 min daily, 6 days a week) or housed under sedentary conditions. The mice received daily subcutaneous injection of ISO (5 mg/kg/d), a nonselective β-adrenergic receptor agonist, during the last 2 weeks of swimming training. Swimming training alleviated ISO-induced cardiac fibrosis in AMPKα2+/+ mice but not AMPKα2-/- mice. Swimming training activated cardiac AMPK in AMPKα2+/+ mice. Furthermore, swimming training attenuated ISO-induced production of reactive oxygen species (ROS) and expression of NADPH oxidase and promoted the expression of antioxidant enzymes in AMPKα2+/+ mice but not AMPKα2-/- mice. In conclusion, swimming training attenuates ISO-induced cardiac fibrosis by inhibiting the NADPH oxidase–ROS pathway mediated by AMPK activation. Our findings provide a new mechanism for the cardioprotective effects of exercise.

[1]  P. Lijnen,et al.  Oxidative stress and transforming growth factor-β1-induced cardiac fibrosis. , 2013, Cardiovascular & hematological disorders drug targets.

[2]  A. Dobrzyń,et al.  Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy. , 2013, American journal of physiology. Endocrinology and metabolism.

[3]  S. Rohrbach,et al.  Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle , 2011, Basic Research in Cardiology.

[4]  A. Dart,et al.  Myocardial oxidative stress contributes to transgenic β2‐adrenoceptor activation‐induced cardiomyopathy and heart failure , 2011, British journal of pharmacology.

[5]  Hyung Gyun Kim,et al.  Metformin inhibits P‐glycoprotein expression via the NF‐κB pathway and CRE transcriptional activity through AMPK activation , 2011, British journal of pharmacology.

[6]  A. Yeh,et al.  Exercise training reduces fibrosis and matrix metalloproteinase dysregulation in the aging rat heart , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Michael D. Schneider,et al.  NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart , 2010, Proceedings of the National Academy of Sciences.

[8]  Yi Zhu,et al.  Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. , 2010, Cardiovascular research.

[9]  G. Su,et al.  Peroxisome proliferator-activated receptors gamma and alpha agonists stimulate cardiac glucose uptake via activation of AMP-activated protein kinase. , 2010, The Journal of nutritional biochemistry.

[10]  J. Sadoshima,et al.  Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes , 2010, Circulation research.

[11]  B. Viollet,et al.  AMPK&agr;2 Deletion Causes Aberrant Expression and Activation of NAD(P)H Oxidase and Consequent Endothelial Dysfunction In Vivo: Role of 26S Proteasomes , 2010, Circulation research.

[12]  J. Coselli,et al.  Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin , 2009, Diabetes.

[13]  M. Sugimachi,et al.  Metformin Prevents Progression of Heart Failure in Dogs: Role of AMP-Activated Protein Kinase , 2009, Circulation.

[14]  A. Lacampagne,et al.  Late exercise training improves non-uniformity of transmural myocardial function in rats with ischaemic heart failure. , 2009, Cardiovascular research.

[15]  S. Jha,et al.  Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure , 2009, Circulation research.

[16]  B. Viollet,et al.  AMP Activated Protein Kinase-α2 Deficiency Exacerbates Pressure-Overload–Induced Left Ventricular Hypertrophy and Dysfunction in Mice , 2008, Hypertension.

[17]  M. Jackson,et al.  Repeated bouts of aerobic exercise lead to reductions in skeletal muscle free radical generation and nuclear factor κB activation , 2008, The Journal of physiology.

[18]  Xiaohua Xu,et al.  Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats. , 2008, Cardiovascular research.

[19]  Natalie J Torok,et al.  Adiponectin Decreases C-Reactive Protein Synthesis and Secretion From Endothelial Cells: Evidence for an Adipose Tissue-Vascular Loop , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[20]  F. Rengo,et al.  Exercise promotes angiogenesis and improves beta-adrenergic receptor signalling in the post-ischaemic failing rat heart. , 2008, Cardiovascular research.

[21]  J. Viña,et al.  Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. , 2008, Free radical biology & medicine.

[22]  H. Chung,et al.  Systemic adaptation to oxidative challenge induced by regular exercise. , 2008, Free radical biology & medicine.

[23]  Y. Fukuyama,et al.  Hypoxia Induces Expression and Activation of AMPK in Rat Dental Pulp Cells , 2007, Journal of dental research.

[24]  Yan Gu,et al.  Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart. , 2007, Cardiovascular research.

[25]  S. Vatner,et al.  Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β2-adrenergic receptor, but not β1-adrenergic receptor , 2007 .

[26]  A. Leask.  TGFβ, cardiac fibroblasts, and the fibrotic response , 2007 .

[27]  Dong Wang,et al.  Long‐term activation of adenosine monophosphate‐activated protein kinase attenuates pressure‐overload‐induced cardiac hypertrophy , 2007, Journal of cellular biochemistry.

[28]  G. Breithardt,et al.  Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice , 2006, Circulation.

[29]  D. Hardie,et al.  AMP‐activated protein kinase – development of the energy sensor concept , 2006, The Journal of physiology.

[30]  Kunihiro Suzuki,et al.  Metformin Inhibits Cytokine-Induced Nuclear Factor &kgr;B Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells , 2006, Hypertension.

[31]  D. Hardie,et al.  AMPK: a key sensor of fuel and energy status in skeletal muscle. , 2006, Physiology.

[32]  D. Sorescu,et al.  NAD(P)H Oxidase 4 Mediates Transforming Growth Factor-β1–Induced Differentiation of Cardiac Fibroblasts Into Myofibroblasts , 2005, Circulation research.

[33]  N. Xu,et al.  Targeted Disruption of Smad4 in Cardiomyocytes Results in Cardiac Hypertrophy and Heart Failure , 2005, Circulation research.

[34]  W. Burns,et al.  Connective Tissue Growth Factor and Cardiac Fibrosis after Myocardial Infarction , 2005, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[35]  Ferhaan Ahmad,et al.  Functional role of AMP‐activated protein kinase in the heart during exercise , 2005, FEBS letters.

[36]  G. Schuler,et al.  Impact of Regular Physical Activity on the NAD(P)H Oxidase and Angiotensin Receptor System in Patients With Coronary Artery Disease , 2005, Circulation.

[37]  G. Shulman,et al.  Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. , 2003, American journal of physiology. Endocrinology and metabolism.

[38]  Matthias Boehm,et al.  Myocardial fibrosis in transforming growth factor‐β1 (TGF‐β1) transgenic mice is associated with inhibition of interstitial collagenase , 2002 .

[39]  J. Sanderson,et al.  Transforming growth factor-β1 expression in dilated cardiomyopathy , 2001 .

[40]  Margaret S. Wu,et al.  Role of AMP-activated protein kinase in mechanism of metformin action. , 2001, The Journal of clinical investigation.

[41]  英志 佐々木.  Metformin prevents progression of heart failure in dogs : role of AMP-activated protein kinase , 2009 .

[42]  S. Vatner,et al.  Inhibition of p38 alpha MAPK rescues cardiomyopathy induced by overexpressed beta 2-adrenergic receptor, but not beta 1-adrenergic receptor. , 2007, The Journal of clinical investigation.

[43]  A. Leask.  TGFbeta, cardiac fibroblasts, and the fibrotic response. , 2007, Cardiovascular research.

[44]  E. Araki,et al.  Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. , 2006, Diabetes.

[45]  A. Nishiyama,et al.  Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. , 2005, Cardiovascular research.

[46]  D. Carling,et al.  Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. , 2002, Diabetes.

[47]  S. Rosenkranz,et al.  Myocardial fibrosis in transforming growth factor-beta(1) (TGF-beta(1)) transgenic mice is associated with inhibition of interstitial collagenase. , 2002, European journal of clinical investigation.