Clinical reviewOxidative stress in obstructive sleep apnea and intermittent hypoxia – Revisited – The bad ugly and good: Implications to the heart and brain
Introduction
Obstructive sleep apnea (OSA) is a highly prevalent breathing disorder in sleep. It is characterized by intermittent hypoxia (IH) leading to blood hypoxemia, hypercapnia, sleep fragmentation, augmented respiratory efforts and increased sympathetic activity [1]. At least 4% and 2% of adult men and women of the general population are diagnosed with OSA and its characteristic symptoms [1]. The prevalence of sleep disordered breathing (SDB) in men and women not displaying day time somnolence may rise up to 24% and 10%, respectively. In obese and elderly populations these values rise to 60% [2]. OSA is also an independent risk factor for cardiovascular morbidity [3], [4], [5], and its prevalence is higher than 60% in patients after acute myocardial infarction (AMI) or stroke [6], [7]. Moreover, the incidence of cardiovascular morbidities such as hypertension, ischemic heart disease, chronic heart failure, arrhythmias and strokes was also shown to be higher than in the general population [3], thus, making OSA a major public health problem by affecting patient's health and quality of life [8]. These latter findings prompted a great number of studies over the past decade aimed at elucidating the impact of OSA on the cardio- and cerebro-vascular system and the associated comorbidities. However, the underlying mechanisms of this association are complex and intertwined and not entirely understood.
Oxidative stress and concomitant inflammation are two of the prominent underlying mechanisms suggested to explain this association. The former is defined as an imbalance between pro-oxidant and anti-oxidant systems resulting in excessive production of reactive oxygen species (ROS). The latter is the body's response to a variety of external as well as internal insults including oxidative stress. This association between oxidative stress and inflammation makes both mechanisms tightly interconnected and exacerbating each other [9], [10].
The involvement of oxidative stress and inflammation and their potential role in promoting cardiovascular morbidity in OSA were extensively described in a review published in this journal in 2003 [11]. In that paper it was suggested that intermittent hypoxia (IH) – the hallmark of OSA – characterized by profound hypoxic episodes followed intermittently by rapid blood oxygenations could be considered analogous to repeated ischemia and reperfusion (I/R) events which result in injury due to flux of ROS during the reperfusion period. I/R injury is a well-established oxidative stress pathway for generating endogenous ROS. It occurs when blood flow to tissues or organs is disrupted and subsequently restored [12]. In a similar manner, the nightly IH cycles OSA patients experience promote ROS production and oxidative stress through these pathways, as shown over the last decade ∗[11], [13].
ROS molecules damage a multitude of vital biomolecules, hence, affecting a vast number of pathologies. Therefore, they are considered “bad/ugly” [14]. Despite their injurious nature, by acting like a double-edged sword, ROS are also considered “good”. While at high quantities ROS promote inflammation and injury, at low or moderate concentrations, ROS act in vital signaling pathways essential for repair and survival. This dual activity is exemplified in various morbidities. In cancer cells, for instance, ROS activate intracellular signaling cascades that maintain the oncogenic phenotype but also possess anti-tumorigenic activity by inducing cell death [15]. Ischemia and reperfusion (I/R) is another well-established phenomenon demonstrating the dual functions of ROS. Although I/R is mostly known as a pathway for eliciting ROS production and subsequent injury, paradoxically, in many instances several brief and intermittent cycles of I/R were shown to exert protective rather than damaging effects. These protective effects, termed ischemic preconditioning (IPC), were demonstrated in various organs including the heart and brain.
Favorable/unfavorable effects of ROS in physiology and pathophysiology are two sides of the same coin [13]. Over the last decade, a great number of studies and reviews were dedicated to the unfavorable effects of IH-associated ROS, as oxidative stress, inflammation and the resultant cardio–cerebro-vascular morbidities in OSA. However, evidence supporting potential protective effects in OSA/SDB/IH is also emerging. It is mainly provided by controlled animal studies mimicking OSA and from recent cellular and epidemiological studies.
This review is aimed at integrating the currently acquired knowledge on redox biology with the currently emerging knowledge on redox biology in OSA/IH while focusing on the complexity of I/R associated damage and repair. This may allow to implement the massively acquired data demonstrating the intertwined unfavorable/favorable effects of redox biology and further stimulate the interest and understanding in this expanding field of research. As such, this may also facilitate the search for detecting potential markers for protective mechanisms associated with IH and OSA/SDB to identify who runs a greater or lower risk for associated morbidities.
Section snippets
Overview
Reactive oxygen species and oxidative stress have long been implicated in initiating and propagating inflammatory responses mediated by leukocyte activation and altered adaptive and immune/inflammatory signaling pathways. Thus, a great number of transcription factors and signaling pathways are modulated by ROS, the most prominent and relevant to OSA being hypoxia inducible factor-1α (HIF-1α), nuclear factor κB (NFκB), activator protein1 (AP1), and nuclear factor (erythroid-derived 2)-like2
ROS/RNS in physiology, pathophysiology and in OSA
In normal physiological conditions there is a homeostasis between the production of ROS and/or reactive nitrogen species (RNS) and the defense mechanisms eliminating them in order to control and maintain a tightly regulated redox (oxidation/reduction) balance for signaling pathways. This redox state is specific for each cell and determines its cellular function. Redox homeostasis is imperative in order to regulate proliferation, differentiation, and cell death (apoptosis) by modulating growth
Protective mechanisms in morbidities associated with I/R
Coronary artery disease, which often results in acute myocardial infarction (AMI), and stroke are two debilitating/fatal diseases and among the leading causes of death worldwide. In both, the prevalence of OSA is higher than 60% [6], [7], [134], [135], [136], [137] and the detrimental effects in both are largely attributed to I/R injury and the associated oxidative stress [138]. Acute myocardial ischemia and infarction can develop when coronary arteries are partially or completely occluded,
Conclusions
Reactive oxygen and nitrogen species (ROS/RNS) have come to occupy an incredibly central role in physiological and pathophysiological conditions. These depend on the type of ROS/RNS produced, the intracellular site of production, the microenvironmental antioxidant activity and their concentrations. At low concentrations, they can act as “good” by regulating vital cellular functions, at higher concentrations they act in a “bad/ugly” manner, by promoting oxidative stress, cellular injury and a
Acknowledgments
This paper is dedicated to Lloyd E. Rigler (1915–2003), who passionately supported sleep medicine research. The support of the Lloyd E. Rigler – Lawrence E. Deutsch Foundation to L. Lavie and P. Lavie is gratefully acknowledged. The assistance of Prof. P. Lavie in reviewing the manuscript and his helpful suggestions are much appreciated. The help of Dr A. Polyakov in preparing the Figures is gratefully acknowledged. I would also like to thank the staff of the Lloyd E. Rigler Sleep Apnea
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