doi: 10.1161/01.RES.0000169466.84402.c1
© 2005 American Heart Association, Inc.
Editorials |
ICE-ing the Heart
From the Scripps Research Institute, La Jolla, Calif.
Correspondence to Dr Roberta A. Gottlieb, Department of Molecular and Experimental Medicine, The Scripps Research Institute MEM220, 10550 North Torrey Pines Road, La Jolla, CA. Email robbieg{at}scripps.edu
See related article, pages 1103–1109
Key Words: caspase-1 • apoptosis • myocardial ischemia • endotoxin • transgenic
In this issue of Circulation Research, Syed et al1 report that overexpression of caspase-1 (ICE) contributes to myocardial ischemia/reperfusion injury. Transgenic mice were generated using the alpha-myosin heavy chair promoter to drive caspase-1 expression in the heart. The mice expressed caspase-1 30-fold more than the nontransgenics. Despite this massive overexpression, no spontaneous caspase activation or apoptosis was noted, and there was no apparent cardiac phenotype. However, endotoxin exposure and ischemia/reperfusion were associated with increased caspase-1 and -3 activation in the transgenic mice, suggesting that caspase-1 contributes to myocardial pathology in these settings. Cell culture studies were used to bolster the notion that caspase-1 activated caspase-3 directly rather than through upstream caspases.
Missing from this study was any analysis of cytokine processing, although the primary role of caspase-1 is to process interleukin-1-beta (IL-1ß) and IL-18, and potentially IL-1
, IL-6, and tumor necrosis factor alpha- (TNF-). Enhanced caspase-1 activity and IL-18 have been reported after myocardial infarction, suggesting a role for caspase-1 in postischemic inflammation and injury.2 Frantz et al who showed that targeted deletion of caspase-1 was associated with reduced postoperative mortality and less left ventricular dilatation after myocardial infarction.3 The authors also noted reduced IL-18 levels and decreased matrix metalloproteinase-3 (MMP-3) in the caspase-1-null animals after myocardial infarction, suggesting that cytokine signaling contributed to the injury process.
Caspase-1 can be processed to the active form by caspase-11,4 which is activated in response to ischemia or endotoxin exposure. Caspase-11 is also capable of activating caspase-3 directly,5 although its significance in the heart is unknown. Caspase-1 is activated by oligomerization with adaptor proteins via the Caspase Recruitment Domain (CARD) domain6 (Caspase-1 can interact with Ipaf, or with one of the 14 known members of the NALP family, which contain 3 domains: a leucine-rich repeat, a NACHT domain, and a pyrin domain, which is bridged to the CARD domain of caspase-1 via a second adaptor, ASC, which contains both a pyrin and a CARD domain. Caspase-5 is also recruited to this multiprotein complex and is believed to participate in caspase-1 activation and IL-1ß processing. Formation of this caspase-1 activation complex, known as the inflammasome, is triggered by lipopolysaccharide binding to its receptor TLR-4. The inflammasome can also be activated by signaling through P2X7 receptors and hypotonic stress. Less is known about the formation of the inflammasome in response to hypoxia or oxidative stress. Whether the composition of the inflammasome complex can vary depending on the stimulus remains to be determined. The net effect is to trigger processing of inflammatory cytokines, particularly IL-1ß; some members of the NALP family also modulate NF-
B activation. Caspase-1 can also form a complex with Nod1 and RIP2/RICK/CARDIAK.7–9 One can expect that cytokine-dependent inflammation and apoptosis of susceptible cells would ensue. This may be particularly relevant to heart failure, in which inflammatory processes and low levels of ongoing cell death prevail.
Whether the caspase-1-dependent apoptosis after ischemia is due to extracellular signaling by the processed cytokines or to intracellular events (caspase-1 activation of caspase-3) remains an open question. The cellular studies conducted by Syed et al1 show that in procaspase-1 transfected cells subjected to hypoxia, there was caspase-3 cleavage in the absence of processing of caspase-8 or -9, which they argue reflects direct activation of caspase-3 by caspase-1. However, it is now widely recognized that caspase-8 and -9 can be active in the absence of proteolytic processing, and that ‘downstream’ caspases, however they become activated, can proteolytically process the initiator caspases. Thus it is difficult to infer activation of caspase-8 or -9 from the demonstration of proteolytic fragments.10 Caspase-1 has been shown to process Bid to its active form, thereby activating the mitochondrial pathway of apoptosis.11 Subsequent work showed that this pathway could be initiated in neuronal cells subjected to ischemia.12 Bid is well known to act as a protease sensor, and can respond to initiator caspases, Granzyme B, cathepsins, and calpains.13,14 Work by Kitsis et al showed marked infarct size reductions in Bid-null mice, pointing to the importance of this mediator regardless of the upstream protease.15
An additional consideration is whether caspase-1 enzymatic activity is required for initiation of apoptosis in this setting. It was shown by Lamkanfi et al16 that caspase-1 could activate NF-B in the absence of protease activity. Given the controversial roles of NF-B signaling in the ischemic and reperfused heart,17,18 future studies using a catalytically inactive mutant of caspase-1 will provide important mechanistic insights.
What does this study tell us about the role of caspase-1 in the myocardium? Overexpression of caspase-1 allowed the investigators to convincingly demonstrate that endotoxin exposure and ischemia can lead to processing of caspase-3. However, such an overexpression study cannot provide insight into the magnitude of this pathway to apoptosis in the nontransgenic heart. Prior studies using a variety of caspase inhibitors have demonstrated at best modest reduction in infarct size, with a greater beneficial effect on remodeling.19,20 The consequences of ongoing low levels of apoptosis are exemplified in the FKBP-caspase-8 transgenic mice,21 which developed dilated cardiomyopathy even in the absence of the dimerizing agent, presumably due to low levels of spontaneous activation of caspase-8. Interestingly, the caspase-1 overexpressing mice do not show evidence of increased apoptosis in the absence of stressors. This may relate to the degree to which each procaspase exhibits spontaneous proteolytic activity. Salvesen has shown that initiator caspases such as caspase-8 and -9 exist as inactive monomers that become activated on dimerization, a process assisted by cofactors. In contrast, executioner caspases such as caspase-3 and -7 exist in the cytosol as dimers, but are inactive until an inhibitory loop covering the catalytic site is removed by proteolysis.10 Caspase-1 requires proteolytic processing for activation,22 which may explain why there is no evidence of spontaneous caspase processing and apoptosis in the caspase-1 transgenic mice despite substantial overexpression, similar to the findings reported for caspase-3 overexpressing mice.23 It is also likely that suppressors of caspase-1, such as Pseudo-ICE and ICEBERG, are present in the heart.24
It is clear that caspase activation—including caspase-1—can lead to apoptosis in the myocardium, but the relative contribution of caspase-dependent cell death to tissue loss after ischemia/reperfusion is less clear. Targeted deletions of caspases can provide some insight, such as the work by Frantz et al in the caspase-1 knockout mouse.3 Inhibition of apoptosis by overexpression of a caspase-9-dominant negative, Bcl-2, or Akt have also been shown to reduce infarct size by 50% to 70%.15,25–28 To the extent that calcium overload and oxidative damage mediate ‘necrotic’ cell death, Bcl-2 and Akt may also protect against necrosis, perhaps explaining why a greater protective effect is seen with these agents than with caspase inhibitors, which have been shown to reduce infarct size by at most 20% to 50%.29–32 Moreover, in some settings, caspase inhibition merely serves to convert apoptosis to necrosis. Finally, because apoptosis is associated with mitochondrial dysfunction, caspase inhibition may not be sufficient to salvage the energetically needy cardiomyocyte.33
This study demonstrates that cardiomyocytes can respond to caspase-1 overexpression and its subsequent activation by initiating apoptosis. Caspase-1 can interact with multiple inflammatory and apoptotic pathways (see Figure). However, further work will be required to determine the extent to which endogenous levels of caspase-1 contribute to myocardial cell death after ischemia, and whether this proceeds via a cytokine-dependent pathway or via cell-autonomous processes. Finally, the role of caspase-1—and its negative regulators—in heart failure, where cytokines are acknowledged to play an important role, merits a closer look.
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. Syed FM, Hahn HS, Odley A, Guo Y, Vallejo JG, Lynch RA, Mann DL, Bolli R, Dorn GW II. Proapoptotic effects of caspase-1/ICE dominate in myocardial ischemia. Circ Res. 2005; 96: 1103–1109.
2. Woldbaek PR, Tonnessen T, Henriksen UL, Florholmen G, Lunde PK, Lyberg T, Christensen G. Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction. Cardiovasc Res. 2003; 59: 122–131.[CrossRef][Medline] [Order article via Infotrieve]
3. Frantz S, Ducharme A, Sawyer D, Rohde LE, Kobzik L, Fukazawa R, Tracey D, Allen H, Lee RT, Kelly RA. Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol. 2003; 35: 685–694.[CrossRef][Medline] [Order article via Infotrieve]
4. Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell. 1998; 92: 501–509.[CrossRef][Medline] [Order article via Infotrieve]
5. Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, Huang Z, Srinivasan A, Tomaselli KJ, Thornberry NA, Moskowitz MA, Yuan J. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol. 2000; 149: 613–622.
6. Martinon F, Tschopp J. Inflammatory caspases: Linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004; 117: 561–574.[CrossRef][Medline] [Order article via Infotrieve]
7. McCarthy JV, Ni J, Dixit VM. RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. J Biol Chem. 1998; 273: 16968–16975.
8. Thome M, Hofmann K, Burns K, Martinon F, Bodmer JL, Mattmann C, Tschopp J. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr Biol. 1998; 8: 885–888.[CrossRef][Medline] [Order article via Infotrieve]
9. Inohara N, del Peso L, Koseki T, Chen S, Nunez G. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. J Biol Chem. 1998; 273: 12296–12300.
10. Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol. 2003; 15: 725–731.[CrossRef][Medline] [Order article via Infotrieve]
11. Guegan C, Vila M, Teismann P, Chen C, Onteniente B, Li M, Friedlander RM, Przedborski S. Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS. Mol Cell Neurosci. 2002; 20: 553–562.[CrossRef][Medline] [Order article via Infotrieve]
12. Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM. Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc Natl Acad Sci U S A. 2003; 100: 16012–16027.
13. Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ, Ellerby LM, Bredesen D, Freeze H, Abrahamson M, Bromme D, Krajewski S, Reed JC, Yin XM, Turk V, Salvesen GS. Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J Biol Chem. 2001; 276: 3149–3157.
14. Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA. Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem. 2001; 276: 30724–30728.
15. Peng C-F, Lee P, DeGuzman A, Miao W, Chandra M, Shirani J, Factor S, Lefer D, Condorelli G, Ardati A, Della Penna K, Zinkel S, Korsmeyer SJ, Tremp G, Zilberstein A, Kitsis RN. Multiple independent mutations in apoptotic signaling pathways markedly decrease infarct size due to myocardial ischemia-reperfusion. Circulation. (Supp), 2001; 104: II-187.
16. Lamkanfi M, Kalai M, Saelens X, Declercq W, Vandenabeele P. Caspase-1 activates nuclear factor of the kappa-enhancer in B cells independently of its enzymatic activity. J Biol Chem. 2004; 279: 24785–24793.
17. Dawn B, Guo Y, Rezazadeh A, Wang OL, Stein AB, Hunt G, Varma J, Xuan YT, Wu WJ, Tan W, Zhu X, Bolli R. Tumor necrosis factor-alpha does not modulate ischemia/reperfusion injury in naive myocardium but is essential for the development of late preconditioning. J Mol Cell Cardiol. 2004; 37: 51–61.[CrossRef][Medline] [Order article via Infotrieve]
18. Onai Y, Suzuki J, Kakuta T, Maejima Y, Haraguchi G, Fukasawa H, Muto S, Itai A, Isobe M. Inhibition of IkappaB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury. Cardiovasc Res. 2004; 63: 51–59.
19. Chandrashekhar Y, Sen S, Anway R, Shuros A, Anand I. Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction. J Am Coll Cardiol. 2004; 43: 295–301.
20. Yarbrough WM, Mukherjee R, Escobar GP, Sample JA, McLean JE, Dowdy KB, Hendrick JW, Gibson WC, Hardin AE, Mingoia JT, White PC, Stiko A, Armstrong RC, Crawford FA, Spinale FG. Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway. J Thorac Cardiovasc Surg. 2003; 126: 1892–1899.
21. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003; 111: 1497–1504.[CrossRef][Medline] [Order article via Infotrieve]
22. Romanowski MJ, Scheer JM, O’Brien T, Mc Dowell RS. Crystal structures of a ligand-free and malonate-bound human caspase-1: Implications for the mechanism of substrate binding. Structure. 2004; 12: 1361–1371.[Medline] [Order article via Infotrieve]
23. Condorelli G, Roncarati R, Ross J Jr, Pisani A, Stassi G, Todaro M, Trocha S, Drusco A, Gu Y, Russo MA, Frati G, Jones SP, Lefer DJ, Napoli C, Croce CM. Heart-targeted overexpression of caspase-3 in mice increases infarct size and depresses cardiac function. Proc Natl Acad Sci U S A. 2001; 98: 9977–9982.
24. Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES. Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 2001; 8: 649–657.[CrossRef][Medline] [Order article via Infotrieve]
25. Brocheriou V, Hagege AA, Oubenaissa A, Lambert M, Mallet VO, Duriez M, Wassef M, Kahn A, Menasche P, Gilgenkrantz H. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med. 2000; 2: 326–333.[CrossRef][Medline] [Order article via Infotrieve]
26. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol. 2001; 280: H2313–H2320.
27. Miao W, Luo Z, Kitsis RN, Walsh K. Intracoronary, adenovirus-mediated Akt gene transfer in heart limits infarct size following ischemia-reperfusion injury in vivo. J Mol Cell Cardiol. 2000; 32: 2397–2402.[CrossRef][Medline] [Order article via Infotrieve]
28. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation. 2001; 104: 330–335.
29. Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation. 1998; 97: 276–281.
30. Holly TA, Drincic A, Byun Y, Nakamura S, Harris K, Klocke FJ, Cryns VL. Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo. J Mol Cell Cardiol. 1999; 31: 1709–1715.[CrossRef][Medline] [Order article via Infotrieve]
31. Huang JQ, Radinovic S, Rezaiefar P, Black SC. In vivo myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia. Eur J Pharmacol. 2000; 402: 139–142.[CrossRef][Medline] [Order article via Infotrieve]
32. Yang W, Guastella J, Huang JC, Wang Y, Zhang L, Xue D, Tran M, Woodward R, Kasibhatla S, Tseng B, Drewe J, Cai SX. MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity. Br J Pharmacol. 2003; 140: 402–412.[CrossRef][Medline] [Order article via Infotrieve]
33. Crow MT, Mani K, Nam Y-J, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res. 2004; 95: 957–970.
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Circ. Res. 2005 96: 1103-1109.
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