This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hare, J. M. Search for Related Content PubMed PubMed Citation Articles by Hare, J. M.

(Circulation Research. 2001;89:198.)
© 2001 American Heart Association, Inc.

Editorial

Oxidative Stress and Apoptosis in Heart Failure Progression

Joshua M. Hare

From the Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Md.

Correspondence to Joshua M. Hare, MD, Johns Hopkins Hospital, Division of Cardiology, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287-6568. E-mail jhare{at}mail.jhmi.edu

Key Words: mitochondria • xanthine oxidase • cytochrome c • superoxide • nitric oxide

The syndrome of congestive heart failure (HF) is the most important cardiovascular disorder in the Western world from public health and health care resource utilization perspectives.¹ Great strides have been made in treating patients with HF through the development of drugs that antagonize neurohormonal activation.² Nevertheless, patients with HF experience clinically meaningful disease progression despite optimal current therapy.

Although the biological mechanisms for progression and ventricular remodeling have yet to be definitively explained, mounting evidence supports the theory that ventricular dysfunction worsens as a consequence of increased reactive oxygen species (ROS) formation, which in turn promotes myocyte apoptosis.³ Myocyte apoptosis is observed in numerous pathological situations including cardiomyopathy,⁴ ischemia,⁵ and transplant rejection⁶ and can be induced experimentally with neurohormonal agonists⁷ or direct generation of superoxide.⁸

In this issue of Circulation Research, Cesselli et al⁹ have examined the linkage between pathways involved in mediating oxidative metabolism and apoptosis in dogs with pacing-induced dilated cardiomyopathy. Using both immunohistochemistry and immunoblotting techniques, the authors track changes in multiple apoptotic pathways including the caspases, mitochondrial cytochrome c release, and proteins involved in DNA damage (see Figure). Importantly, induction of these changes precedes the development of left ventricular (LV) dysfunction, providing additional strong support, but not definitive proof, that apoptosis participates in the progression of LV remodeling. In addition, a new signaling molecule, p66^shc, linking oxidative stress and apoptosis is demonstrated to be upregulated with pacing-induced HF.¹⁰ p66^shc is an oxidant stress–induced, proapoptotic proto-oncogene known to be activated by phosphorylation in response to stimuli such as H₂O₂, UV radiation, or epidermal growth factor. Transgenic disruption of p66^shc or inactivation of its ability to be phosphorylated confers resistance to oxidative damage and prolongs life in mice.¹⁰ The observations made by Cesselli et al⁹ add further insight into the signaling pathways linking myocardial apoptosis with cellular ability to cope with oxidative stress. The major strength of the work is the comprehensive evaluation of multiple steps in proapoptotic signaling cascades, which demonstrates clearly that these pathways are activated as HF and LV dysfunction develop. Although this association is convincing, it does not prove that apoptosis is an essential feature of HF pathogenesis. This will remain an open question until interventions that inhibit apoptosis specifically are shown to affect the natural history of HF. Nevertheless, this work raises many interesting issues.

View larger version (29K): [in this window] [in a new window]   Central role for ROS in myocardial apoptosis. Cellular sources of ·O2- include mitochondria, XO, and NAD(P)H oxidase. Elevated ·O2- production in heart failure contributes to the release of cytochrome c from mitochondria and the activation of p66shc, both of which participate in initiating or promoting apoptotic cascades. Thus, formation of ROS represents a central phenomenon for apoptosis in the failing heart. p53 and p21 are proapoptotic and antiapoptotic molecules, respectively, that are activated by p66shc. Bax and Bak are members of the BCL-2 protein family that participate in mitochondrial membrane pore-opening responsible for cytochrome c release into the cytoplasm. Fas is a cell surface receptor that activates apoptotic cascades when stimulated by its receptor.

Whether mitochondria are initiators or secondary victims of apoptosis continues to be hotly debated.¹¹ In either case, it is of great mechanistic interest that mitochondria are an important source of ROS in HF. Mitochondria generate ATP by a series of oxidation-reduction reactions mediated by respiratory complexes NADH-CoQ reductase (complex I), succinate-CoQ reductase (complex II), cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV) (see Figure). Cytochrome c is a 13-kDa heme-containing protein that serves as an electron acceptor facilitating electron transfer from complex III to complex IV. The transfer of electrons allows the respiratory complexes to generate an electrochemical gradient by pumping protons (through complexes I, III, and IV; see Figure) from the mitochondrial matrix into the inner membrane, and this gradient (proton-motive force) provides the energy for ATP synthesis by F₀ F₁ ATPase. Superoxide (^·O₂^-) generation in mitochondria occurs as a result of incomplete reduction of O₂ to H₂O. Whereas some ^·O₂^- formation occurs during physiological oxidative phosphorylation (and, to compensate, mitochondria contain superoxide dismutase and other antioxidant defenses), in HF, mitochondrial ^·O₂ production is greatly augmented.¹² The clear demonstration that mitochondria generate increased ROS in HF favors a central rather than bystander role for these organelles in apoptosis.

Mitochondria contribute to or initiate apoptosis through the release of cytochrome c, which in turn stimulates apoptosis activating factor (Apaf-1) and caspases 9 and 3. Atlante et al,¹³ in an in vitro model of neuronal toxicity, have shown that the formation of ROS may be the proximate cause of cytochrome c release from mitochondria, in a process that involves a pore opened by members of the BCL-2 family of proteins, Bax and Bak. Loss of cytochrome c likely disrupts the electron transport chain and may contribute to further ^·O₂^- production. The result is more oxidative stress, and a potential vicious cycle that further promotes apoptosis.

The central role of the mitochondrion in apoptosis and the fact that mitochondrial ATP synthesis is the major source of energy in cardiac myocytes suggest that disorders of apoptosis and energy metabolism may be linked pathologically. Although this linkage is speculative, there is strong evidence that oxidative stress may also impair energy metabolism in HF. This is of particular significance given that uncoupling of energy utilization and ventricular performance represents a hallmark lesion in the failing heart.¹⁴ In this regard, xanthine oxidase (XO), a newly appreciated source of oxidative stress in HF that generates ^·O₂^- as a byproduct of purine metabolism, has augmented activity in the failing canine heart. XO inhibition with allopurinol restores cardiac efficiency toward normal,¹⁵ by both increasing myocardial contractility and reducing oxygen consumption. Additionally, both allopurinol and vitamin C potentiate ß-adrenergic inotropic responses in animals and humans.^16,17 Two additional observations support a linkage between mitochondrial ability to produce ATP (maintenance of the mitochondrial membrane potential) and apoptosis. First, ATP-sensitive K⁺ channel agonists offset both oxidative stress–induced loss of the mitochondrial membrane potential and apoptosis.¹⁸ Second, nitric oxide synthase is present in mitochondria where it not only physiologically inhibits O₂ consumption at complex IV but also preserves mitochondrial membrane potential and inhibits apoptosis.^19,20 Future work will be required to explore the interaction between apoptosis and cardiac energy metabolism.

Is the current totality of evidence sufficient to conclude definitively that oxidative stress–induced apoptosis is a final common pathway for progressive LV dysfunction? It is important to consider that apoptosis may not be the whole story behind net loss of myocytes in progressive LV dysfunction. As apoptosis is a basic mechanism important in embryogenesis and tissue repair,²¹ perhaps it contributes to myocardial restoration after injury. This possibility is especially relevant given reports from the same group that myocytes can undergo mitosis and are therefore not terminally differentiated.^22,23 Thus, disease progression in HF may reflect an imbalance between myocyte loss and replacement. In a setting where cells are being appropriately replaced, apoptosis may actually represent a favorable process whereby damaged cells are removed. Future work will need to examine the relative rates of myocyte loss and regeneration in HF models, as well as the role oxidative stress plays in stimulating or inhibiting myocyte mitosis.

The work by Cesselli et al⁹ introduces the proto-oncogene p66^shc into the increasingly complicated array of biochemical events that link oxidative stress with cardiac programmed cell death. To obtain a comprehensive view of how LV dysfunction progresses, future work will need to separate adaptive from nonadaptive consequences of apoptosis. In addition, it will be important to consider the broader spectrum of roles played by oxidant signaling in HF such as depression of myocardial energetics. Understanding these potentially reversible processes offers hope for novel treatment strategies for HF.

Acknowledgments

This work was supported by NIH grant RO1 HL-65455 and a Paul Beeson Physician Faculty Scholars in Aging Research Award.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Adams KFJ. New epidemiologic perspectives concerning mild-to-moderate heart failure. Am J Med. . 2001; 110 (suppl 7A): 6S–13S.
2. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. . 2001; 344: 1651–1658.[Abstract/Free Full Text]
3. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end-stage heart failure. N Engl J Med. . 1996; 335: 1182–1189.[Abstract/Free Full Text]
4. Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD, Dal Bello B, Semigran MJ, Bielsa-Masdeu A, Dec GW, Israels S, Ballester M, Virmani R, Saxena S, Kharbanda S. Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci U S A. 1999;96:8144–8149.
5. Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkki LM, Tikkanen I. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. . 2001; 280: H2726–H2731.[Abstract/Free Full Text]
6. Xu B, Sakkas LI, Slachta CA, Goldman BI, Jeevanandam V, Oleszak EL, Platsoucas CD. Apoptosis in chronic rejection of human cardiac allografts. Transplantation. . 2001; 71: 1137–1146.[Medline] [Order article via Infotrieve]
7. Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of ß₁- and ß₂-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation. . 1999; 100: 2210–2212.[Abstract/Free Full Text]
8. Siwik DA, Tzortzis JD, Pimental DR, Chang DL, Pagano PJ, Singh K, Sawyer DB, Colucci WS. Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circ Res. . 1999; 85: 147–153.[Abstract/Free Full Text]
9. Cesselli D, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. Oxidative stress–mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res. . 2001; 89: 279–286.[Abstract/Free Full Text]
10. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66^shc adaptor protein controls oxidative stress response and life span in mammals. Nature. . 1999; 402: 309–313.[Medline] [Order article via Infotrieve]
11. Finkel E. The mitochondrion: is it central to apoptosis? Science. . 2001; 292: 624–626.[Free Full Text]
12. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res. . 1999; 85: 357–363.[Abstract/Free Full Text]
13. Atlante A, Calissano P, Bobba A, Azzariti A, Marra E, Passarella S. Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death. J Biol Chem. . 2000; 275: 37159–37166.[Abstract/Free Full Text]
14. Wolff MR, De Tombe PP, Harasawa Y, Burkhoff D, Bier S, Hunter WC, Gerstenblith G, Kass DA. Alterations in left ventricular mechanics, energetics, and contractile reserve in experimental heart failure. Circ Res. . 1992; 70: 516–529.[Abstract/Free Full Text]
15. Ekelund UEG, Harrison RW, Shokek O, Thakkar RN, Tunin RS, Senzaki H, Kass DA, Marbán E, Hare JM. Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. Circ Res. . 1999; 85: 437–445.[Abstract/Free Full Text]
16. Ukai T, Cheng CP, Tachibana H, Igawa A, Zhang ZS, Cheng HJ, Little WC. Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure. Circulation. . 2001; 103: 750–755.[Abstract/Free Full Text]
17. Mak S, Newton GE. Vitamin C augments the inotropic response to dobutamine in humans with normal left ventricular function. Circulation. . 2001; 103: 826–830.[Abstract/Free Full Text]
18. Akao M, Ohler A, O’Rourke B, Marbán E. Mitochondrial ATP -sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res. . 2001; 88: 1267–1275.[Abstract/Free Full Text]
19. Clementi E, Brown GC, Foxwell N, Moncada S. On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci U S A. . 1999; 96: 1559–1562.[Abstract/Free Full Text]
20. Beltran B, Mathur A, Duchen MR, Erusalimsky JD, Moncada S. The effect of nitric oxide on cell respiration: a key to understanding its role in cell survival or death. Proc Natl Acad Sci U S A. . 2000; 97: 14602–14607.[Abstract/Free Full Text]
21. Fisher SA, Langille BL, Srivastava D. Apoptosis during cardiovascular development. Circ Res. . 2000; 87: 856–864.[Abstract/Free Full Text]
22. Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. . 2001; 344: 1750–1757.[Abstract/Free Full Text]
23. Liu Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze TH, Anversa P. Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest. . 1995; 73: 771–787.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				A. P. Saliaris, L. C. Amado, K. M. Minhas, K. H. Schuleri, S. Lehrke, M. St. John, T. Fitton, C. Barreiro, C. Berry, M. Zheng, et al. Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1328 - H1335. [Abstract] [Full Text] [PDF]

				K. M. Minhas, R. M. Saraiva, K. H. Schuleri, S. Lehrke, M. Zheng, A. P. Saliaris, C. E. Berry, K. M. Vandegaer, D. Li, and J. M. Hare Xanthine Oxidoreductase Inhibition Causes Reverse Remodeling in Rats With Dilated Cardiomyopathy Circ. Res., February 3, 2006; 98(2): 271 - 279. [Abstract] [Full Text] [PDF]

				S. Bertuglia, A. Giusti, and P. Del Soldato Antioxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation Am J Physiol Gastrointest Liver Physiol, March 1, 2004; 286(3): G437 - G443. [Abstract] [Full Text] [PDF]

				R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface Circ. Res., November 14, 2003; 93 (10): e124 - e135. [Abstract] [Full Text] [PDF]

				F. Qin, J. Shite, and C.-s. Liang Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H822 - H832. [Abstract] [Full Text] [PDF]

				T. P. Cappola, L. Cope, A. Cernetich, L. A. Barouch, K. Minhas, R. A. Irizarry, G. Parmigiani, S. Durrani, T. Lavoie, E. P. Hoffman, et al. Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy Physiol Genomics, June 24, 2003; 14(1): 25 - 34. [Abstract] [Full Text] [PDF]

				R. J. Scheubel, M. Tostlebe, A. Simm, S. Rohrbach, R. Prondzinsky, F. N. Gellerich, R.-E. Silber, and J. Holtz Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2174 - 2181. [Abstract] [Full Text] [PDF]

				Z.-Q. Zhao and J. Vinten-Johansen Myocardial apoptosis and ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 438 - 455. [Abstract] [Full Text] [PDF]

				T. Date, A. J Belanger, S. Mochizuki, J. A Sullivan, L. X Liu, A. Scaria, S. H Cheng, R. J Gregory, and C. Jiang Adenovirus-mediated expression of p35 prevents hypoxia/reoxygenation injury by reducing reactive oxygen species and caspase activity Cardiovasc Res, August 1, 2002; 55(2): 309 - 319. [Abstract] [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hare, J. M. Search for Related Content PubMed PubMed Citation Articles by Hare, J. M.