Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation

Physiol Rev 99: 311–379, 2019 Published October 31, 2018; doi:10.1152/physrev.00036.2017 SOURCES OF VASCULAR NITRIC OXIDE AND REACTIVE OXYGEN SPECIES AND THEIR REGULATION X Jesús Tejero, Sruti Shiva, and Mark T. Gladwin Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Tejero J, Shiva S, Gladwin MT. Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation. Physiol Rev 99: 311–379, 2019. Published October 31, 2018; doi:10.1152/physrev.00036.2017.—Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the mainte- Lnance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concen- tration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreduc- tases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the thera- peutic challenges and opportunities for the management of NO and ROS in cardiovascular disease. I. INTRODUCTION 311 These include oxygen radicals and peroxides, such as super- ·Ϫ II. NITRIC OXIDE GENERATION AND... 312 oxide (O2 ) and hydrogen peroxide (H2O2), nitrogen rad- · III. SUPEROXIDE AND HYDROGEN... 327 ical species, such as NO and nitrogen dioxide (NO2 ), and Ϫ IV. OTHER ROS 344 other species, such as peroxynitrite (ONOO ) and hypo- Ϫ V. CROSS-TALK BETWEEN ROS AND... 346 chlorite (ClO ). The species containing nitrogen are often VI. CONCLUDING REMARKS:... 347 treated separately as reactive nitrogen species (RNS). It is worth indicating that despite being long considered toxic I. INTRODUCTION species, most of these molecules have been shown to exert important signaling functions (249, 778, 937, 960). There- Nitric oxide (NO) is a small free radical molecule with fore, the role of many of these molecules in health and critical signaling roles. The discovery of the function of NO disease is related to their production rates, steady-state con- in the vascular endothelium as endothelium-derived relax- centrations, and the ability of the cellular antioxidant sys- ing factor led to the awarding of the 1998 Nobel Prize to tems to modulate their activity. Drs. Furchgott, Ignarro and Murad (36, 324, 449, 491, 716). The functions of NO in mammalian systems extend In general, dysregulated production of ROS/RNS, as is the beyond vascular signaling and are relevant in all organ sys- case for NO, leads to oxidative stress and deleterious con- tems, including but not limited to neuronal signaling, and sequences for living systems. However, as pointed out host defense (448, 659, 738). above, these molecules often have important signaling roles at low concentrations. For instance, the differences in re- A number of oxygen-related species of high chemical reac- sponse to NO at varying concentrations have attracted con- tivity are referred to as reactive oxygen species (ROS). siderable attention. It has been shown that low levels (pM/ 0031-9333/19 Copyright © 2019 the American Physiological Society 311 Downloaded from www.physiology.org/journal/physrev by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on November 29, 2018. Copyright © 2019 the American Physiological Society. All rights reserved. TEJERO ET AL. nM) are physiological and related to the activation of high donors or supplementing with NOS substrates to reverse affinity primary binding targets such as soluble guanylyl endothelial dysfunction have had limited success. The use of cyclase (sGC) and cytochrome c oxidase (433, 863). An general antioxidants for the treatment of oxidative stress emerging paradigm proposes that intermediate levels (50– has also failed in most cases. Recent advances in the field 300 nM) can activate a range of positive and negative re- have provided many clues on why these approaches have sponses from wound healing to oncogenic pathways (938). been unsuccessful. We will discuss these and other relevant Higher concentrations of NO (Ͼ1 ␮M) can lead not only to physiological and pathophysiological issues and indicate oxidative stress but also nitrative and nitrosative stress via how advances in basic biochemistry of the generation of the generation of peroxynitrite and nitrosating species (411, NO/ROS have evolved our understanding and set new di- 412, 938, 939), and in combination with oxygen, can trig- rections in the field. ger posttranslational modification of proteins, lipids, and DNA (277, 433, 938). In this review, we will present the biology of NO and ROS in the cardiovascular system with special emphasis on their The production of adequate levels of NO in the vascular routes of formation, chemistry, mode of action, and dys- endothelium is critical for the regulation of blood flow and regulation in vascular disease. The formation pathways of vasodilation, as will be discussed at length in this review NO and the mechanisms of NO signaling will be discussed (299, 565, 573, 600, 786). In this context, it has become in sect. II. The proteins and biological systems generating increasingly appreciated that oxygen levels can impact the hydrogen peroxide and superoxide are treated in sect. III. oxidation/reduction properties of different proteins and Other ROS of particular relevance in the vascular system regulate NO levels (FIGURE 1) (367, 578, 595, 931). For are discussed in sect. IV. Section V will study the cross-talk example, nitric oxide synthases (NOSs) produce NO using between NO- and ROS-generating systems. Finally, in sect. L-arginine and molecular oxygen (O2) as substrates. Thus, VI, we will discuss the current challenges and opportunities under hypoxic or anoxic conditions, the generation of NO for the treatment of cardiovascular disease through the reg- via NOS is compromised. However, a number of proteins ulation of NO and ROS levels in pathological conditions. that are involved in oxidative processes at basal oxygen levels can become de facto reductases as oxygen is depleted. The biological role of this transition is particularly promi- II. NITRIC OXIDE GENERATION AND nent in the case of heme- and molybdopterin-containing VASCULAR FUNCTION proteins such as hemoglobin (Hb), myoglobin (Mb), and xanthine oxidase (XO) (185, 575, 578, 862, 880, 945, The generation of sufficient NO levels to regulate the resis- 990). Clinical intervention through these pathways contin- tance of the blood vessels and hence the maintenance of an ues attracting intense research. adequate blood flow is critical to the healthy performance of the vasculature (277, 299, 573, 600, 786). A number of The concept of oxygen-regulated oxidation and reduction mechanisms are involved in both the generation of NO and processes in the metabolism of NO is not only relevant to the response to NO signaling in the vasculature. In this NO generation but also to the scavenging of NO in the section, we will overview the mammalian proteins involved vasculature (FIGURE 1). In this regard, the role of globins in the generation and sensing of NO in the cardiovascular like ␣-Hb and cytoglobin (Cygb) as catalytic NO dioxyge- system. The production of NO in basal conditions is largely nases that scavenge NO is a topic of current research (25, regulated by the activity of endothelial NOS (eNOS) in the 593, 594, 898). vascular endothelium (324, 449, 716). Nevertheless, the contribution of other agents cannot be ignored. For in- The translation of our knowledge about the biology of NO stance, nitrite reduction by heme proteins can mediate hy- and ROS has encountered significant challenges. For in- poxic vasodilation and other physiological responses (367, stance, initial attempts to enhance NO levels using NO 591, 968); neuronal NOS (nNOS) and inducible NOS (iNOS) can provide compensatory NO generation or exac- erbated RNS synthesis (386, 444, 547, 704, 727). In this - NO NO3 study, we will review NO synthases and other NO-generating biological systems. Fe2+-O 2 - NO2 NO A. Oxygen-Dependent Nitric Oxide Synthesis O 2 Fe2+ The canonical pathways of NO formation rely on the spe- cialized NOS enzymes.

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