doi: 10.1161/01.CIR.0000143048.05940.0D
(Circulation. 2004;110:1178-1179.)
© 2004 American Heart Association, Inc.
Editorial |
Exogenous Thioredoxin Reduces Inflammation in Autoimmune Myocarditis
From the Division of Cardiology, Departments of Medicine and Pathology, The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Charles J. Lowenstein, 950 Ross Building, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. E-mail clowenst{at}jhmi.edu
Key Words: Editorials • myocarditis • inflammation • oxygen
Levels of reactive oxygen species (ROS) are tightly regulated in mammalian cells. A variety of enzymes produce ROS, including NAD(P)H oxidase, xanthine oxidase, glucose oxidase, myeloperoxidase, the family of nitric oxide synthases, and mitochondrial enzymes.1–4 Low levels of ROS such as superoxide or hydrogen peroxide regulate highly specific targets.5,6 In the cardiovascular system, for example, ROS serve as signaling molecules, mediating vascular endothelial growth factor signal transduction, activating matrix metalloproteinases, and regulating cell cycle phosphatases. Host defenses that protect against oxidative stress include small antioxidant molecules such as ascorbate, 
-tocopherol, glutathione, and thioredoxin (Trx), as well as antioxidant enzymes such as superoxide dismutase, catalase, paraoxonase, glutathione reductase, glutathione peroxidase, and Trx reductase.
See p 1276
However, excessive oxidative stress—caused by either increased ROS production or inadequate antioxidant defenses—can lead to cardiovascular diseases. For example, genetic deficiency of glutathione peroxidase-1 is associated with increased levels of vascular hydrogen peroxide and arterial thrombosis.7,8 Another example of an imbalance in oxidant stress occurs when elevated levels of angiotensin II trigger excess ROS production by the vascular NAD(P)H oxidase Mox1, contributing to decreased nitric oxide bioavailability, endothelial dysfunction, and atherogenesis.9,10 Additionally, increased levels of ROS generated by xanthine oxidase in the heart impair cardiac energetics, playing a role in the development of cardiomyopathy.11,12 Finally, ROS may play a critical role in autoimmune myocarditis.
Autoimmunity is surprisingly common in patients with cardiomyopathy: Up to 20% of all idiopathic dilated cardiomyopathies are associated with autoantibodies and other autoimmune markers.13 Triggers of autoimmune myocarditis include (1) molecular mimicry, in which viral antigens structurally similar to myocardial antigens activate lymphocytes to recognize and attack the host, and (2) cryptic epitopes, in which myocardial inflammation alters the processing and presentation of normal host antigens.14,15 These exogenous or endogenous antigens then stimulate an immune response directed against the host myocardium, driven by B and T lymphocytes, natural killer cells, neutrophils, and monocytes.16 Effectors released by autoreactive immune cells include perforin, granzyme B, and autoantibodies directed against myocytes. Neutrophils and monocytes infiltrating into inflamed myocardium express NAD(P)H oxidase and myeloperoxidase, enzymes capable of generating high levels of ROS.
ROS may play a role at multiple steps in autoimmune pathways. Cryptic epitopes can be produced by highly reactive hydroxyl anions that oxidize amino acids or DNA bases, generating novel antigens such as 8-hydroxyguanosine. Cryptic epitopes also may be produced by cytotoxic radicals that damage cells, releasing sequestered antigens. ROS can activate antigen presentation by dendritic cells. Excessive oxidant stress can regulate the activity of intracellular transcription factors, leading to the release of inflammatory cytokines and chemokines that regulate leukocyte trafficking into the heart. Finally, ROS can kill cells by necrosis or apoptosis, leading to further myocardial injury.
In this issue of Circulation, Liu and colleagues17 examine the effects of Trx therapy for autoimmune myocarditis in mice. Building on prior published work demonstrating that Trx protects the myocardium from ischemia and drug toxicity,18,19 these investigators hypothesized that Trx should inhibit myocarditis by decreasing protein oxidation, chemokine signaling, and leukocyte trafficking. In an elegant set of experiments, the authors administered exogenous Trx or decreased endogenous Trx in mice injected with myosin. The results of their study support their hypothesis: Trx does indeed decrease myocarditis, but the mechanism of action is unclear.
Trx might affect any one of a number of pathways that lead to autoimmune myocarditis:
- Scavenging ROS. One simple explanation for the beneficial effect of exogenous Trx is that Trx scavenges radicals such as hydroxyl radical and hydrogen peroxide that would otherwise oxidize proteins, lipids, and DNA.20–22 Supporting this theory, Liu and colleagues17 found in their present study that Trx decreases levels of the oxidized DNA base 8-hydroxyguanosine. Trx thus may ameliorate myocarditis by blocking the formation of novel oxidized antigens or by blocking the release of sequestered antigens from cardiac myocytes injured by cytotoxic levels of ROS.
- Reducing oxidized targets. Trx is a component of an antioxidant system that includes Trx, Trx reductase, and NADPH.20–22 The reduced form of Trx interacts with oxidized proteins, reduces the target protein, and is itself oxidized. Trx reductase then uses the reducing equivalents of NADPH to convert oxidized Trx to reduced Trx, which then can reduce additional targets. For example, reduced Trx interacts with and reduces specific transcription factors such as nuclear factor-
B, p53, and AP1.20–22 Liu and colleagues17 found in their present study that Trx treatment suppressed expression of macrophage inflammatory protein-1, which is regulated by nuclear factor-B. Trx thus may inhibit myocardial inflammation by modulating expression of inflammatory genes.
- Modulating signal transduction cascades. Trx also has redox-independent effects. Trx can bind to apoptosis signal–related kinase 1 (ASK-1), inducing ubiquitination and degradation of ASK1, thereby decreasing apoptosis mediated by ASK1.23,24 Trx also interacts with vitamin D3–upregulated protein, which may modulate cell differentiation and growth.25,26 The present study by Liu et al17 did not examine the effect of Trx on myocardial apoptosis but did detect less myocyte necrosis in Trx-treated mice. Trx may thus limit myocarditis by promoting cell survival.
The study by Liu et al17 also raises intriguing but unanswered questions. The authors showed that treatment with mutant Trx lacking active site cysteine residues has no effect on myocarditis.17 Is the redox activity of Trx responsible for its beneficial effects, or are the cysteine residues needed to interact with the targets of Trx? Cells exposed to oxidant stress can secrete Trx; other cells can transport Trx from the extracellular space into the cytoplasm.20–22 Does Trx act outside or inside cardiovascular cells to alleviate myocardial inflammation? If exogenous Trx acts inside its target cells, how does Trx gain access to the intracellular compartment? Finally, what are the specific protein targets of Trx in autoimmune myocarditis?
Whatever the precise mechanism, the demonstration that Trx ameliorates myocardial inflammation has important clinical implications. Antioxidant therapy may be beneficial in patients with autoimmune myocarditis and perhaps with other autoimmune disease as well. Additional preclinical studies are needed before Trx therapy is ready for clinical trials. Nevertheless, these intriguing and important animal studies support the concept that the balance of oxidative stress and antioxidant defenses is an important therapeutic target in autoimmune diseases.
Acknowledgments
Supported by grants from the National Institutes of Health (R01 HL63706, R01 HL074061, P01 HL65608, P01 HL56091), American Heart Association (EIG 0140210N), the Ciccarone Center, and the John and Cora H. Davis Foundation.
Footnotes
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
References
1. Loscalzo J. Oxidative stress in endothelial cell dysfunction and thrombosis. Pathophysiol Haemost Thromb. 2002; 32: 359–360.[CrossRef][Medline] [Order article via Infotrieve]
2. Loscalzo J. Oxidant stress: a key determinant of atherothrombosis. Biochem Soc Trans. 2003; 31: 1059–1061.[Medline] [Order article via Infotrieve]
3. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury, part II: animal and human studies. Circulation. 2003; 108: 2034–2040.
4. Fukai T, Folz RJ, Landmesser U, Harrison DG. Extracellular superoxide dismutase and cardiovascular disease. Cardiovasc Res. 2002; 55: 239–249.
5. Xu D, Rovira II, Finkel T. Oxidants painting the cysteine chapel: redox regulation of PTPs. Dev Cell. 2002; 2: 251–252.[CrossRef][Medline] [Order article via Infotrieve]
6. Finkel T. Oxidant signals and oxidative stress. Curr Opin Cell Biol. 2003; 15: 247–254.[CrossRef][Medline] [Order article via Infotrieve]
7. Freedman JE, Loscalzo J, Benoit SE, Valeri CR, Barnard MR, Michelson AD. Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis. J Clin Invest. 1996; 97: 979–987.[Medline] [Order article via Infotrieve]
8. Kenet G, Freedman J, Shenkman B, Regina E, Brok-Simoni F, Holzman F, Vavva F, Brand N, Michelson A, Trolliet M, Loscalzo J, Inbal A. Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke. Arterioscler Thromb Vasc Biol. 1999; 19: 2017–2023.
9. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury, part I: basic mechanisms and in vivo monitoring of ROS. Circulation. 2003; 108: 1912–1916.
10. Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999; 401: 79–82.[CrossRef][Medline] [Order article via Infotrieve]
11. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. 2004; 555: 589–606.
12. Sawyer DB, Colucci WS. Mitochondrial oxidative stress in heart failure: "oxygen wastage" revisited. Circ Res. 2000; 86: 119–120.
13. Caforio AL, Goldman JH, Haven AJ, Baig KM, Libera LD, McKenna WJ. Circulating cardiac-specific autoantibodies as markers of autoimmunity in clinical and biopsy-proven myocarditis. The Myocarditis Treatment Trial Investigators. Eur Heart J. 1997; 18: 270–275.
14. Rose NR. Viral damage or ’molecular mimicry’-placing the blame in myocarditis. Nat Med. 2000; 6: 631–632.[CrossRef][Medline] [Order article via Infotrieve]
15. Lanzavecchia A. How can cryptic epitopes trigger autoimmunity? J Exp Med. 1995; 181: 1945–1948.
16. Huber SA. Autoimmunity in myocarditis: relevance of animal models. Clin Immunol Immunopathol. 1997; 83: 93–102.[CrossRef][Medline] [Order article via Infotrieve]
17. Liu W, Nakamura H, Shioji K, Tanito M, Oka S, Ahsan A, Son A, Ishii Y, Kishimoto C, Yodoi J. Thioredoxin-1 ameliorates myosin-induced autoimmune myocarditis by suppressing chemokine expression and leukocyte chemotaxis in mice. Circulation. 2004; 110: 1276–1283.
18. Turoczi T, Chang VW, Engelman RM, Maulik N, Ho YS, Das DK. Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1. J Mol Cell Cardiol. 2003; 35: 695–704.[CrossRef][Medline] [Order article via Infotrieve]
19. Aota M, Matsuda K, Isowa N, Wada H, Yodoi J, Ban T. Protection against reperfusion-induced arrhythmias by human thioredoxin. J Cardiovasc Pharmacol. 1996; 27: 727–732.[CrossRef][Medline] [Order article via Infotrieve]
20. Yamawaki H, Haendeler J, Berk BC. Thioredoxin: a key regulator of cardiovascular homeostasis. Circ Res. 2003; 93: 1029–1033.
21. Hirota K, Nakamura H, Masutani H, Yodoi J. Thioredoxin superfamily and thioredoxin-inducing agents. Ann N Y Acad Sci. 2002; 957: 189–199.[Medline] [Order article via Infotrieve]
22. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000; 267: 6102–6109.[Medline] [Order article via Infotrieve]
23. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. Embo J. 1998; 17: 2596–2606.[CrossRef][Medline] [Order article via Infotrieve]
24. Liu Y, Min W. Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. Circ Res. 2002; 90: 1259–1266.
25. Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem. 1999; 274: 21645–21650.
26. Schulze PC, De Keulenaer GW, Yoshioka J, Kassik KA, Lee RT. Vitamin D3–upregulated protein-1 (VDUP-1) regulates redox-dependent vascular smooth muscle cell proliferation through interaction with thioredoxin. Circ Res. 2002; 91: 689–695.
Related Article:
Circulation 2004 110: 1276-1283.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||