Review ArticleReactive oxygen species in cardiovascular disease
Introduction
In the early 20th century, the “rate-of-living hypothesis” was derived from observations that animals with higher metabolic rates were characterized by shorter life spans, implying that a species’ metabolic rate ultimately determines its life expectancy. In 1956, Denham Harman proposed a “free radical theory” that endogenous oxygen radicals were generated in cells over time, resulting in cumulative cellular damage targeting DNA, protein, lipids, and other components of the cell [1]. Because cardiovascular disease is a manifestation of aging, researchers have attempted to elucidate the relation between cardiovascular disease and oxidative stress caused by free radicals.
Section snippets
Clinical studies of antioxidants in vascular disease
Initially, these studies focused on how antioxidants may influence the clinical course of atherosclerosis and cardiovascular disease. Numerous clinical trials have been performed to examine the potential for preventing cardiovascular disease using antioxidant therapies (please see Table 1). The term “cardiovascular disease” encompasses the major clinical end-points related to the heart and vascular system, including myocardial infarction (MI; heart attack), ischemic heart disease (MI and
Selected sources of ROS in cardiovascular disease
A variety of enzymatic and nonenzymatic processes can generate ROS in mammalian cells. Some of the most important sources are the mitochondrial respiratory chain, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidase, lipoxygenase, uncoupled nitric oxide synthase (NOS), and myeloperoxidase (MPO), and these systems are depicted in Fig. 2. There is evidence linking each of these sources with CVD pathology (Table 2) and, as a consequence, we discuss each in turn below.
Detection of ROS in cardiovascular disease
One strategy to determine the role of ROS in CVD involves looking for experimental evidence of oxidative reactions in clinical populations. A major challenge in monitoring ROS in biologic systems is the highly reactive nature of the compounds in question. Fluorescent probes have been designed that can detect individual ROS [163], and electron spin resonance probes exist that can provide information about the activity and location of free radical reactions [164]. However, these tools are limited
Studies of ROS involving the myocardium
In addition to the vascular component of cardiovascular disease, considerable morbidity and mortality also result from pathology in the myocardium related to ischemia–reperfusion injury and heart failure, the former being an important manifestation of heart attack and stroke and the latter a consequence of prior myocardial function. Thus, there have been attempts to determine the impact of ROS on the heart directly. In the paragraphs below, we focus on studies that have provided insight into
Conclusion
Overall, there are considerable data linking oxidative stress and ROS to the physiology and pathophysiology of CVD. Initial attempts to ameliorate manifestations of CVD with simple antioxidant strategies have not proven helpful, probably because ROS have important and diverse physiological roles. As our understanding of how the sources of ROS are regulated and how specific ROS interact with their targets has grown, we have developed a greater understanding of how ROS modulate cardiovascular
Acknowledgments
This study was supported by NIH Grants HL092122, HL098407, and HL 081587 and Diabetes Endocrinology Research Center Grant DK32520. Dr. Sugamura is supported by the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad (2009) and the Uehara Memorial Foundation Research Fellowship (2010), Japan.
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