Invited ReviewImpact of exercise training on redox signaling 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.
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