Elsevier

Food and Chemical Toxicology

Volume 62, December 2013, Pages 107-119
Food and Chemical Toxicology

Invited Review
Impact of exercise training on redox signaling in cardiovascular diseases

https://doi.org/10.1016/j.fct.2013.08.035Get rights and content

Highlights

  • Oxidant stress has an adverse impact on the pathophysiology of cardiovascular diseases.

  • Redox signaling regulates exercise-training-mediated cardioprotection.

  • Exercise training counteracts oxidant stress in cardiovascular pathologies.

Abstract

Reactive oxygen and nitrogen species regulate a wide array of signaling pathways that governs cardiovascular physiology. However, oxidant stress resulting from disrupted redox signaling has an adverse impact on the pathogenesis and progression of cardiovascular diseases. In this review, we address how redox signaling and oxidant stress affect the pathophysiology of cardiovascular diseases such as ischemia–reperfusion injury, hypertension and heart failure. We also summarize the benefits of exercise training in tackling the hyperactivation of cellular oxidases and mitochondrial dysfunction seen in cardiovascular diseases.

Introduction

Cardiovascular disease remains a major public health problem; acute myocardial infarction, hypertension and heart failure are among the leading causes of morbidity and mortality worldwide (Gerczuk and Kloner, 2012). According to the World Health Organization, over 7 million people die of cardiovascular disease every year (WHO, 2011), and this circumstance may however be more critical considering that the prevalence of cardiovascular diseases is expected to rise as the mean age of the population increases. Therefore, the fundamental mechanisms responsible for the pathophysiology and progression of cardiovascular diseases, as well as the development of pharmacological and non-pharmacological therapies, must be extensively studied.

Cardiovascular diseases are commonly described as multifactorial diseases characterized by activation of neurohumoral systems (i.e. sympathetic and renin–angiotensin–aldosterone systems), inflammation, cellular reprogramming and bioenergetics dysfunction (Chen et al., 2008, Churchill et al., 2010, Ferreira et al., 2008, Shen and Young, 2012). Common to these processes is increased oxidant stress, characterized by excessive generation of reactive oxygen and nitrogen species (ROS and RNS, respectively) and reduced antioxidant capacity. The purpose of this review is to outline the role of oxidant stress in cardiovascular diseases, and summarize evidence suggesting that exercise training counteracts the oxidant stress that is commonly observed.

Section snippets

Reactive oxygen and nitrogen species

ROS and RNS are classes of reactive radical and non-radical molecules that play a critical role in the cardiovascular physiology and pathophysiology. In an attempt to acquire stability, these unstable species tend to donate or steal electrons from other molecules, such as lipids, carbohydrates, proteins and nucleic acids, which usually results in structural remodeling of its molecular targets. ROS and RNS can be either friends or foes depending on concentration, location and context.

Oxidant stress in the cardiovascular system

The term “oxidant stress” describes conditions that result from the spatio-temporal imbalance between free radical generation [reactive atoms/ions/molecules with unpaired electrons or unstable bonds] and its detoxification through enzymatic and non-enzymatic systems. Studies using cell culture and experimental animal models clearly support the role of oxidant stress in the onset and progression of cardiac diseases (Churchill et al., 2005, Churchill and Szweda, 2005, Yogalingam et al., 2013).

Redox signaling

Based on a large body of evidence, it is now recognized that under physiological conditions, the reversible reduction–oxidation of molecules, a process termed “redox signaling”, positively regulates the activity of a vast array of intracellular proteins and signaling pathways including protein phosphorylation, proteolysis, regulation of transcription factors, cellular differentiation, and proliferation (Droge, 2002, Stowe and Camara, 2009). In the cardiovascular system, the redox signaling

Mitochondria

Mitochondria are membrane-enclosed organelles that use an electrochemical gradient [generated across the mitochondrial inner membrane] to produce ATP (adenosine triphosphate), at the expense of O2 as a final electron acceptor. Mitochondria have been considered the major source of cellular ROS in mammals under physiological conditions (Fig. 1) (Figueira et al., 2013). Moreover, increased mitochondrial ROS generation underlies several cardiovascular diseases (Palaniyandi et al., 2010).

During

Antioxidant systems

To counteract the excessive generation of ROS and RNS, cells present a variety of antioxidant systems that scavenge these reactive molecules to non-toxic species. Antioxidants can be defined as any substance that, when available at low concentration compared with those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate (Halliwell and Gutteridge, 1995). Enzymatic antioxidants sources include SOD, catalase, glutathione peroxidase (GPX), thioredoxin and

Exercise training and redox signaling

Physical inactivity along with poor cardiorespiratory fitness are known factors associated with elevated mortality and morbidity worldwide (Carnethon et al., 2005, Nauman et al., 2012, Wisloff et al., 2005). A large case-control study attributed 12% of coronary artery disease to physical inactivity (Yusuf et al., 2004). Therefore, exercise training has been widely recommended as an important strategy not only to improve aerobic capacity but also for the prevention and treatment of several

Conclusion

Evidence from experimental and human studies supports a decisive role for oxidant stress and redox signaling in cardiovascular homeostasis and disease. Exercise training plays a positive role in virtually all redox aspects of cardiac and vascular pathophysiology. However, the molecular mechanisms by which exercise training improves redox homeostasis in cardiovascular diseases remain unknown and warrant future investigation.

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors thank Theodore Davis for critical reading of the manuscript. This study was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (2012/05765-2) and Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico (470880/2012-0) grants to J.C.B.F. J.C.C. holds a fellowship from Fundação de Amparo a Pesquisa do Estado de São Paulo (2012/14416-1). J.C.B.F holds a scholarship from Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico, Brasil.

References (192)

  • I. Dalle-Donne

    Familial amyotrophic lateral sclerosis (FALS): emerging hints from redox proteomics. highlight commentary on: “Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice – a model of familial amyotrophic lateral sclerosis”

    Free Radical Biology & Medicine

    (2007)
  • W. Doehner et al.

    Xanthine oxidase and uric acid in cardiovascular disease: clinical impact and therapeutic options

    Seminars in Nephrology

    (2011)
  • J.C. Ferreira et al.

    BetaIIPKC and epsilonPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure

    Journal of Molecular and Cellular Cardiology

    (2011)
  • J.C. Ferreira et al.

    Pharmacological inhibition of betaIIPKC is cardioprotective in late-stage hypertrophy

    Journal of Molecular and Cellular Cardiology

    (2011)
  • J.C. Ferreira et al.

    Angiotensin receptor blockade improves the net balance of cardiac Ca(2+) handling-related proteins in sympathetic hyperactivity-induced heart failure

    Life Sciences

    (2011)
  • M. Fransen et al.

    Role of peroxisomes in ROS/RNS-metabolism: implications for human disease

    Biochimica et Biophysica Acta

    (2012)
  • H. Fujita et al.

    SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice

    Metabolism, Clinical and Experimental

    (2012)
  • P.Z. Gerczuk et al.

    An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials

    Journal of the American College of Cardiology

    (2012)
  • R.A. Gottlieb

    Cytochrome P450: major player in reperfusion injury

    Archives of Biochemistry and Biophysics

    (2003)
  • B. Halliwell et al.

    The definition and measurement of antioxidants in biological systems

    Free Radical Biology & Medicine

    (1995)
  • R. Harrison

    Structure and function of xanthine oxidoreductase: where are we now?

    Free Radical Biology & Medicine

    (2002)
  • Y. Higashi et al.

    Exercise and endothelial function: role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients

    Pharmacology & Therapeutics

    (2004)
  • Y.S. Ho et al.

    Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury

    The Journal of Biological Chemistry

    (2004)
  • S.J. Hong et al.

    Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry

    Experimental Gerontology

    (2007)
  • K. Husain

    Physical conditioning modulates rat cardiac vascular endothelial growth factor gene expression in nitric oxide-deficient hypertension

    Biochemical and Biophysical Research Communications

    (2004)
  • K. Husain et al.

    Oxidative injury due to chronic nitric oxide synthase inhibition in rat: effect of regular exercise on the heart

    Biochimica et Biophysica Acta

    (2002)
  • D.P. Jones et al.

    Redox state of glutathione in human plasma

    Free Radical Biology & Medicine

    (2000)
  • S.M. Kanzok et al.

    The thioredoxin system of the malaria parasite Plasmodium falciparum. Glutathione reduction revisited

    The Journal of Biological Chemistry

    (2000)
  • V. Adams et al.

    Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease

    Circulation

    (2005)
  • V.D. Antonenkov et al.

    Peroxisomes are oxidative organelles

    Antioxidants & Redox Signaling

    (2010)
  • A. Ascensao et al.

    Exercise as a beneficial adjunct therapy during Doxorubicin treatment – role of mitochondria in cardioprotection

    International Journal of Cardiology

    (2011)
  • B.S. Avner et al.

    H2O2 alters rat cardiac sarcomere function and protein phosphorylation through redox signaling

    American Journal of Physiology

    (2010)
  • B.S. Avner et al.

    Myocardial infarction in mice alters sarcomeric function via post-translational protein modification

    Molecular and Cellular Biochemistry

    (2012)
  • A.V. Bacurau et al.

    Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training

    Journal of Applied Physiology

    (2009)
  • K. Bedard et al.

    The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology

    Physiological Reviews

    (2007)
  • R. Belardinelli et al.

    Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome

    Circulation

    (1999)
  • M. Bertagnolli et al.

    Exercise training reduces sympathetic modulation on cardiovascular system and cardiac oxidative stress in spontaneously hypertensive rats

    American Journal of Hypertension

    (2008)
  • V. Bezzerides et al.

    Saying yes to exercise and NO to cardiac injury

    Circulation Research

    (2011)
  • P. Bianchi et al.

    Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury

    Circulation

    (2005)
  • J. Blanco-Rivero et al.

    Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats

    Journal of Hypertension

    (2013)
  • D.K. Bowles et al.

    Exercise training improves cardiac function after ischemia in the isolated, working rat heart

    The American Journal of Physiology

    (1992)
  • D.K. Bowles et al.

    Exercise training improves metabolic response after ischemia in isolated working rat heart

    Journal of Applied Physiology

    (1994)
  • K. Brieger et al.

    Reactive oxygen species: from health to disease

    Swiss Med. Wkly

    (2012)
  • M. Brioschi et al.

    Redox proteomics identification of oxidatively modified myocardial proteins in human heart failure: implications for protein function

    PLoS ONE

    (2012)
  • G.C. Brown et al.

    Nitric oxide and mitochondrial respiration in the heart

    Cardiovascular Research

    (2007)
  • P.C. Brum et al.

    Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function

    Brazilian Journal of Medical and Biological Research

    (2011)
  • P.C. Brum et al.

    Exercise training increases baroreceptor gain sensitivity in normal and hypertensive rats

    Hypertension

    (2000)
  • G. Budas et al.

    Identification of epsilon PKC targets during cardiac ischemic injury

    Circulation Journal

    (2012)
  • C.R. Bueno et al.

    Aerobic exercise training improves skeletal muscle function and Ca2+ handling-related protein expression in sympathetic hyperactivity-induced heart failure

    Journal of Applied Physiology

    (2010)
  • J.W. Calvert

    Cardioprotective effects of nitrite during exercise

    Cardiovascular Research

    (2011)
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