Beyond reactive oxygen species: aldehydes as arbitrators of alarm and adaptation.
نویسندگان
چکیده
Reactive oxygen species (ROS) are generated either during oxidative metabolism or in defense against pathogens. Their production is increased further by tissue injury or disease. Extensive evidence accumulated during the last 30 years provides compelling evidence that ROS-induced damage is a significant cause of cardiovascular injury and dysfunction. A variety of enzymatic and nonenzymatic antioxidants have evolved to protect against the constant onslaught of ROS, and these defenses respond deftly to changes in ROS generation or to the generation of secondary oxidation products. In this issue of Circulation Research, Endo et al1 report that increased mitochondrial accumulation of aldehydes derived from lipid oxidation protects against myocardial ischemia/reperfusion injury. These findings put a new twist on our view of the oxidant–antioxidant balance in the heart and underscore the importance of hormesis in which mild exposure to a stressor elicits an adaptive response that increases resistance to subsequent stress. Understanding how endogenous defense mechanisms are enhanced by stress response signaling could lead to the development of new strategies for combating oxidative stress. Most biological ROS are highly reactive and, therefore, short-lived. The ones with the greatest reactivity, such as the hydroxyl and alkoxyl radicals, have the shortest life span. As a result, the damage they induce is likely to be restricted to their site of origin and, therefore, of limited significance. Hence, it has long been suspected that ROS generate secondary products that spread injury and amplify damage. Which molecules can amplify and propagate ROS-initiated injury? Although many possibilities exist, one likely class of molecules may be aldehydes generated by the oxidation of unsaturated lipids. With the exception of antioxidants such as vitamin E or glutathione, unsaturated lipids are the most likely targets of ROS. When oxidized, these lipids generate a plethora of bioactive molecules, of which aldehydes are among the most reactive and abundant products. Being engendered by the violent fragmentation of their lipid parents, these aldehydes possess high reactivity. However, they are more stable than ROS, so they can diffuse to sites distant from their site of injury, thereby propagating oxidative injury. Moreover, these aldehydes possess a rich variety of structural features or they acquire additional ones by conjugating with receptive nucleophiles, which allows them to be recognized by cell constituents as signaling molecules. Aldehydes generated from oxidized lipids such as malondialdehyde, 4-hydroxy-trans-2-nonenal (HNE), and 1-palmitoyl-2oxovaleroyl phosphatidyl choline (POVPC) have been detected in almost all tissues that have experienced oxidative injury. They are found in ischemic, hypertrophic, and failing hearts; in atherosclerotic lesions and restenotic vessels; in apoptotic cells; and in damaged mitochondria.2 Nevertheless, it is unclear whether they are simply markers of oxidative stress (footprints of a disruptive presence long gone) or whether they are active instruments of injury and sounders of alarm signaling. How does one study the active role of aldehydes in adaptation or injury? One approach is to examine aldehyde metabolism. Like ROS, aldehydes are metabolized and detoxified by several nonenzymatic and enzymatic processes (see the Figure). Previous work has shown that in most cells aldehydes are either reduced (to alcohols), oxidized (to acids), or conjugated with cellular nucleophiles such as glutathione, carnosine ( -alanine-L-histidine), or proteins. Several enzymes involved in metabolizing these aldehydes have been identified.2 In cardiovascular tissue, aldose reductase (AR) catalyzes the reduction of both HNE and POVPC. Oxidation of aldehydes is catalyzed by aldehyde dehydrogenases (ALDHs) and glutathione conjugation is facilitated by glutathione S-transferases. By converting aldehydes to less reactive products, these enzymes prevent the direct toxicity of aldehydes; however, metabolic conversion could also enhance stability of aldehydes and thereby augment their ability to stimulate cell signaling. Hence, investigations into the role of aldehyde-metabolizing enzymes in modulating outcomes of oxidative injury could provide one avenue for understanding the role of aldehydes as mediators of oxidative stress– related signaling. In keeping with the view that ROS-mediated injury could be attributed in part to lipid-derived aldehydes, it has been shown that modulation of aldehyde metabolism profoundly affects cardiovascular injury. For example, inhibition of the aldehyde-metabolizing enzyme AR abolishes the late phase of ischemic preconditioning3 and exacerbates atherogenesis.4 Moreover, treatment with small molecule activators of ALDH2 to stimulate the metabolism of cytotoxic aldehydes reduces infarct size by 60%,5 indicating that much of the damage inflicted by ischemia/reperfusion could be attributed to aldehydes generated in the ischemic heart. In contrast, Endo et al1 report that transgenic expression of an Aldh2 gene containing a single nucleotide polymorphism (Aldh2*2), with The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville, Ky. Correspondence to Aruni Bhatnagar, Diabetes and Obesity Center, University of Louisville, Delia Baxter Building, Rm 421, 580 South Preston St, Louisville, KY 40202. E-mail [email protected] (Circ Res. 2009;105:1044-1046.) © 2009 American Heart Association, Inc.
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عنوان ژورنال:
- Circulation research
دوره 105 11 شماره
صفحات -
تاریخ انتشار 2009