CuZn superoxide dismutase deficiency: culprit of accelerated vascular aging process.

Impairment of endothelium-dependent responses is an early landmark of endothelial dysfunction in blood vessels with aging and/or cardiovascular diseases.1 A critical manifestation of endothelial dysfunction is the reduced bioavailability of NO, a key vascular protective molecule and an independent predictor of cardiovascular events.2 Hence, stimuli decreasing vascular NO bioavailability manifest impaired endothelium-dependent relaxation. Aging is associated with marked changes in the cardiovascular system, especially at the level of the vascular wall.3 Both structural and functional changes can take place at the level of the endothelium, vascular smooth muscle cell (VSMC), and the extracellular matrix of blood vessels. Endothelial thickening and altered endothelium-dependent responses have been reported in aged animals. Clinical studies have also shown that endothelium-dependent relaxation of both conduit and resistance vessels declines progressively with age. In contrast, endothelium-independent relaxation to sodium nitroprusside is unaffected by aging, suggesting that the impaired relaxation with age is primarily because of the dysfunctional endothelium, rather than VSMC contraction.3 Although the mechanisms underlying the aging-induced endothelial dysfunction are complex and incompletely understood, oxidative stress is a key contributor.4 Exposure of endothelial cells to increased levels of reactive oxygen species (ROS) during the aging process makes them a prime target for oxidative stress. As the first and initiating oxygen free radical in the ROS chain, superoxide (O2 ) consumption of NO is one of the most important mechanisms of endothelial dysfunction.5 Vascular cells possess multifaceted protective mechanisms against the toxic effects of ROS.4–6 Among them, the 3 superoxide dismutase (SOD) isoforms, the cytosolic copper zinc SOD (CuZnSOD, SOD-1), mitochondrial manganese SOD (MnSOD, SOD-2), and extracellular SOD (EC-SOD, SOD-3), have evolved as the key enzymatic defense system for converting O2 to hydrogen peroxide (H2O2) and molecular oxygen (O2). The importance of SOD on endothelial function is highlighted by studies of SODdeficient mice that manifest profound endothelial dysfunction (Table). These different isoforms, characterized by their prosthetic metal ion and cellular localization, play distinctive roles. MnSOD knockout mice exhibit neonatal lethality,8 because the vast majority of cellular ROS (estimated at 90%) emanate from the mitochondria.9 EC-SOD, the only extracellular isoform, is a copper/zinc-containing enzyme mainly secreted by VSMCs and binds to the endothelial surface via its heparin-binding domain in the extracellular matrix.7 MnSOD and EC-SOD play pivotal roles in the regulation of the oxidant status in the mitochondria and vascular interstitium, respectively.7 Consistent with this notion, recent studies have shown that gene transfer of MnSOD or EC-SOD significantly suppresses elevated vascular O2 levels in hypertension and diabetes, respectively.10–12 The CuZn-SOD, also a copper/zinc-containing dimer SOD, is the predominant form of SOD in blood vessels, because it accounts for 50% to 80% of total SOD activity.7 The normal activity of CuZnSOD is necessary to limit increases in superoxide, allowing release of NO from endothelium and normal endothelium-dependent relaxation. Deficiency in CuZnSOD results in increased levels of vascular O2 and peroxynitrite (ONOO ) and subsequently impaired endothelium-dependent relaxation in large arteries and microvessels, as well as hypertrophy of cerebral arterioles.13,14 In contrast, overexpression of CuZnSOD decreases vascular O2 in some models of cardiovascular diseases and improves endothelial function.7 However, in the context of the vascular aging process, very little is known about the precise role of CuZn-SOD. In the current issue of Hypertension, Didion et al15 report that total SOD activity is significantly lower in aorta of young heterozygous CuZnSOD-deficient mice (ie, CuZnSOD / ) compared with that of age-matched wild-type mice (ie, 7 month old) and aged CuZnSOD / mice (ie, 22 to 24 months old), accompanied by increased O2 levels. Endotheliumdependent relaxation of the carotid artery is markedly impaired in CuZnSOD / but not wild-type mice with aging. This is the first time that striking vascular phenotype in aging heterozygous CuZn-SOD-deficient mice has been described, which adds new and important insights into the mechanisms underlying CuZnSOD protection of the endothelial cell from dysfunction and cell loss. In addition, tempol (an O2 scavenger) restores endothelium-dependent responses in CuZnSOD / mice with aging, providing strong evidence that the impaired response to acetylcholine in old CuZnSOD / mice is mediated by O2 in a reversible manner. These findings suggest that normal CuZnSOD expression protects endothelial function and that deficiency in a single copy of the gene accelerates endothelial dysfunction with aging. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Pharmacology and Neurology, Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing, Mich. Correspondence to Alex F. Chen, Department of Pharmacology and Toxicology, B403 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. E-mail [email protected] (Hypertension. 2006;48:1026-1028.) © 2006 American Heart Association, Inc.