Sad heart from no SOD.

The superoxide dismutases (SODs), which catalyze the dismutation of 2 superoxide anions to hydrogen peroxide and oxygen, represent major antioxidant mechanisms in single-cell organisms, plants, bacteria and eukaryotes. In mammalian cells, there are 3 forms of SOD that include the mitochondrial manganese SOD (MnSOD or SOD2), the cytoplasmic SOD that is a copper/zinc-containing enzyme (Cu/Zn SOD or SOD1), and an extracellular SOD that is also a copper/zinc-containing enzyme (ecSOD or SOD3). The ecSOD is unique in that it is actively secreted via the trans-Golgi network and binds to glycosaminoglycans in the vascular extracellular matrix and to the extracellular protein fibrillin 5.1 In most tissues, the amount of ecSOD is very small, on the order of 1% to 5% of the total SOD. In contrast, blood vessels, the lung, and to a lesser extent, the heart contain substantial amounts of this enzyme. The ecSOD is therefore of particular interest to investigators interested in cardiovascular and pulmonary biology. Overexpression of ecSOD protects mice against lung damage, and mice lacking ecSOD are predisposed to lung injury caused by hyperoxia. Between 30% and 50% of the total SOD in blood vessels is in this extracellular form, and mice lacking this enzyme have vascular dysfunction and are predisposed to hypertension.2 In cardiovascular tissues and, likely the lung, an important role of the SODs is to protect NO against oxidative inactivation by superoxide. Both NO and superoxide are free radicals with unpaired electrons in their outer orbitals and react with one another in a diffusion-limited fashion. Studies in which the Cu/ZnSODs (SOD1 and SOD3) have been pharmacologically inhibited have shown that NO cannot be released from the endothelium without being oxidatively degraded.3 Thus, these enzymes play a role in promoting vasodilatation and sustaining the protective roles of NO in the vascular wall. In the case of the ecSOD, its extracellular location allows it to act as a shepherd guiding NO on its way from one cell to another (Figure). Of note, and to be discussed later, the product of the reaction of superoxide and NO is the strong oxidant peroxynitrite. In the present issue of Hypertension, Lu et al4 have shown that the ecSOD plays this shepherd’s role in the heart. These investigators subjected wild-type and ecSOD / mice to transaortic constriction (TAC) to cause left ventricular pressure overload. The responses to this challenge were strikingly different between the wild-type and ecSOD-deficient mice. The degree of hypertrophy, ventricular dilatation, and myocardial fibrosis was markedly increased in mice lacking ecSOD. TAC also caused a striking increase in collagen I and III, atrial natriuretic factor, and matrix metalloproteinases-2 and -9 in ecSOD / mice that was either much less or absent in wild-type mice. These findings demonstrate that the ecSOD is essential for protecting the heart against pressure overload and implicate extracellular superoxide in the genesis of heart failure. The question is how does this occur? Superoxide is short lived and charged, such that it does not cross cell membranes in substantial quantities. How then, does extracellular superoxide increase the expression of proteins like atrial natriuretic factor, matrix metalloproteinases, or collagens? How can it change the ratio of reduced:oxidized glutathione, which are largely intracellular molecules? How can it turn on a hypertrophy program in these hearts? The answers to these questions are speculative; however, there are a couple of important hints from the study by Lu et al.4 First, as shown in Figure 4 of their article, the authors found a striking increase of nitrotyrosine in ecSOD / mouse hearts subjected to TAC as detected by Western analysis. Nitrotyrosines were once thought to be a footprint of peroxynitrite’s reaction with tyrosines in various proteins; however, it is now clear that they can also be formed via a reaction of hydrogen peroxide with peroxidases and nitrite, leading to formation of higher oxides of nitrogen that react with protein tyrosines. In the setting of ecSOD deficiency, however, the most likely reason for nitrotyrosine formation is almost certainly increased peroxynitrite formation in the extracellular space. The half-life of peroxynitrite and its diffusion distance is substantially greater than that of superoxide, and unlike superoxide, it can cross cell membranes.5 It is therefore very likely that when formed in the extracellular space of hearts in ecSOD / mice after TAC, it entered myocytes and vascular cells where it proceeded to create havoc. Thus, the ecSOD, although outside the cell, protects it from intracellular onslaught by peroxynitrite. A second major hint from Lu et al’s article4 is shown in their Figure 3. As evident from the Western blots in panel A, protein levels of the intracellular SOD1 in ecSOD / mouse hearts were identical to those of wild-type mice both at baseline and after TAC. In contrast to this, SOD1 activity was diminished by almost half in ecSOD / hearts after TAC. Why did this occur? It has been well documented that peroxynitrite can react with SOD1 and reduce its activity by almost exactly as much as that observed by Lu et al.4 This is associated with formation of a histidinyl radical, indicative of interplay with the copper center of the enzyme that is The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Medicine, Emory University School of Medicine and Atlanta Veterans’ Administration Hospital, Atlanta, Ga. Correspondence to David G. Harrison, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, Room 319 WMB, Atlanta, GA 30322. E-mail [email protected] (Hypertension. 2008;51:28-30.) © 2007 American Heart Association, Inc.