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• W2096238505 abstract "EDITORIAL FOCUSGenetic modification of vascular endothelial function as therapeutic strategy in heart failureChen-Fuh Lam, and Zvonimir S. KatusicChen-Fuh Lam, and Zvonimir S. KatusicPublished Online:01 Aug 2005https://doi.org/10.1152/ajpheart.00374.2005MoreSectionsPDF (95 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat in patients with chronic heart failure, endothelial dysfunction contributes to increased systemic vascular resistance, decreased exercise tolerance, and reduced tissue perfusion. One of the better-characterized mechanisms responsible for endothelial dysfunction is the increased production of superoxide anions (9). In the vascular wall, superoxide anions are generated mainly through the activation of NADPH oxidase by the univalent reduction of oxygen (4, 11). Under physiological conditions, superoxide anions are scavenged by superoxide dismutases (CuZn-SOD, extracellular SOD, and MnSOD) producing a relatively stable reactive oxygen species H2O2 (11). H2O2 has been shown to be an important endothelium-derived hyperpolarizing factor that mediates endothelium-dependent relaxation in the resistance arteries (8). High concentrations of superoxide anions chemically inactivate endothelium-derived nitric oxide (NO) to form a potent oxidant peroxynitrite (7). The NO-superoxide anion reaction rate of 6.7 × 109 M−1s−1 is three times faster than the reaction between superoxide anion and SOD (4). Therefore, increased production of superoxide anions consumes NO causing endothelial dysfunction.Bauersachs and colleagues (1) provided evidence that heart failure causes vascular endothelial dysfunction by increased superoxide anion production. Superoxide anions were mainly generated in the vascular smooth muscle, because removal of endothelium did not affect free radical production (1). Furthermore, this same group demonstrated that high levels of superoxide anions in the aortas of rats with heart failure were produced by the upregulated NADPH oxidase (12). Activation of renin-angiotensin humoral system is responsible for the induction of NADPH oxidase and the subsequent increased superoxide anion production in the vasculature (1). Vitamin C supplementation reduces vascular superoxide anion production and potentiates endothelial function of patients with chronic heart failure (3, 5). It has also been speculated that in heart failure, therapeutic effects of angiotensin-converting enzyme inhibitors, angiotensin II antagonists, spironolactone, hydralazine, and statins are mediated, in part, by a decrease in vascular oxidative stress (2, 9, 10).In this issue of American Journal of Physiology-Heart and Circulatory Physiology, Iida and colleagues (6) report a series of elegant experiments demonstrating the vascular protective effect of extracellular SOD (ecSOD) gene transfer in a rat model of heart failure. Four days after ecSOD transfer, the generation of superoxide anions was reduced, and endothelial function in the aortas and mesenteric arteries of rats with heart failure was significantly improved. One of the most striking findings in this study is that improved endothelial function in mesenteric arteries was derived from enhanced vascular release of H2O2. These results point to two important molecular targets for vascular protection in heart failure: 1) ecSOD scavenges superoxide anions thereby potentiating endothelium-dependent relaxation responses by increasing bioavailability of NO, and 2) restoration of endothelium-bound ecSOD enzymatic activity enables the vasculature to release sufficient amounts of H2O2 that contribute to the normalization of vasodilation (Fig. 1). Thus, in addition to scavenging of superoxide anions, optimal release of H2O2 in the resistant arteries may be an important mechanism responsible for maintenance of normal systemic vascular resistance. Indeed, endothelial function in small vessels is largely dependent on production and release of endothelium-derived hyperpolarizing factor. This study also provides important evidence demonstrating a critical role of ecSOD heparin-binding domain for the therapeutic effect of this antioxidant enzyme. Based on this observation it appears likely that mutation in the ecSOD heparin-binding domain may contribute to the pathogenesis of heart failure. This attractive hypothesis remains to be tested in future studies. Fig. 1.Scavenging of superoxide anions (O2−·) by gene transfer of endothelium-bound extracellular superoxide dismutase (ecSOD) potentiates endothelium-dependent relaxation response by 1) increasing bioavailability of nitric oxide (NO·) and 2) increased production of H2O2.Download figureDownload PowerPointREFERENCES1 Bauersachs J, Bouloumie A, Fraccarollo D, Hu K, Busse R, and Ertl G. Endothelial dysfunction in chronic mayocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production. Circulation 100: 292–298, 1999.Crossref | PubMed | ISI | Google Scholar2 Bauersachs J, Heck M, Fraccarollo D, Hildemann SK, Ertl G, Wehling M, and Christ M. Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide synthase expression. J Am Coll Cardiol 39: 351–358, 2002.Crossref | PubMed | ISI | Google Scholar3 Ellis GR, Anderson RA, Lang D, Blackman DJ, Morris RHK, Morris-Thurgood J, McDowell IFW, Jackson SK, Lewis MJ, and Frenneaux MP. Neutrophil superoxide anion-generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy. J Am Coll Cardiol 36: 1474–1482, 2000.Crossref | PubMed | ISI | Google Scholar4 Faraci FM and Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol 24: 1367–1373, 2004.Crossref | PubMed | ISI | Google Scholar5 Hornig B, Arakawa N, Kohler C, and Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 97: 363–368, 1998.Crossref | PubMed | ISI | Google Scholar6 Iida S, Chu Y, Francis J, Weiss RM, Gunnett CA, Faraci FM, and Heistad DD. Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure. Am J Physiol Heart Circ Physiol 289: H000–H000, 2005.Google Scholar7 Li JM and Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287: R1014–R1030, 2004.Link | ISI | Google Scholar8 Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, and Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarization factor in mice. J Clin Invest 106: 1521–1530, 2000.Crossref | PubMed | ISI | Google Scholar9 Munzel T and Harrison DG. Increased superoxide in heart failure: a biochemical baroreflex gone awry. Circulation 100: 216–218, 1999.Crossref | PubMed | ISI | Google Scholar10 Schafer A, Fraccarollo D, Tas P, Schmidt I, Ertl G, and Bauersachs J. Endothelial dysfunction in congestive heart failure: ACE inhibition vs angiotensin II antagonism. Eur J Heart Fail 6: 151–159, 2004.Crossref | PubMed | ISI | Google Scholar11 Taniyama Y and Griendling KK. Reactive oxygen species in the vasculature. Hypertension 42: 1075–1081, 2003.Crossref | PubMed | ISI | Google Scholar12 Widder J, Behr T, Fraccarollo D, Hu K, Galuppo P, Tas P, Angermann CE, Ertl G, and Bauersachs J. Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase-dependent. Cardiovasc Res 63: 161–167, 2004.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: Z. S. Katusic, Dept. of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 (e-mail [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByPotential of Omega-3 Polyunsaturated Fatty Acids in Managing Chemotherapy- or Radiotherapy-Related Intestinal Microbial Dysbiosis19 December 2018 | Advances in Nutrition, Vol. 10, No. 1Designing Heart Performance by Gene TransferJennifer Davis, Margaret V. Westfall, Dewayne Townsend, Michael Blankinship, Todd J. Herron, Guadalupe Guerrero-Serna, Wang Wang, Eric Devaney, and Joseph M. Metzger1 October 2008 | Physiological Reviews, Vol. 88, No. 4 More from this issue > Volume 289Issue 2August 2005Pages H518-H519 Copyright & PermissionsCopyright © 2005 by the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00374.2005PubMed16014612History Published online 1 August 2005 Published in print 1 August 2005 Metrics" @default.
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