Influence of the terminal complement-complex on reperfusion injury, no-reflow and arrhythmias: a comparison between C6-competent and C6-deficient rabbits

Ito, Wulf; Schäfer, Hansjörg; Bhakdi, Sucharit; Klask, R; Hansen, Sirje; Schaarschmidt, S.; Schofer, Joachim; Hugo, F; Hamdoch, T.; Mathey, D

doi:10.1016/0008-6363(96)00082-x

Cited by 47 publications

(30 citation statements)

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“…However, C1s-INH-248 treatment retarded C 5b-9 deposition and tissue injury. In a similar approach of myocardial ischemia and reperfusion in C6-deficient rabbits, reduction of myocardial necrosis was related to a reduction in C 5b-9 deposition (29).…”

Section: Discussionmentioning

confidence: 96%

Novel Small Molecule Inhibitor of C1s Exerts Cardioprotective Effects in Ischemia-Reperfusion Injury in Rabbits

Buerke

Schwertz

Seitz

et al. 2001

The Journal of Immunology

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Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 ± 2.5 vs 8.9 ± 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 ± 6.8 vs 45.1 ± 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 ± 0.23 vs 0.4 ± 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.

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Section: Discussionmentioning

confidence: 96%

Novel Small Molecule Inhibitor of C1s Exerts Cardioprotective Effects in Ischemia-Reperfusion Injury in Rabbits

Buerke

Schwertz

Seitz

et al. 2001

The Journal of Immunology

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“…Each of these activities serves to block the subsequent activation of new C3 molecules (fH acts by promoting decay acceleration of the alternative pathway C3 convertase and as a cofactor for factor I-mediated proteolysis of C3b). Subsequent studies using C6-deficient animals or animals treated with anti-C5 Ab or C5a receptor antagonist indicate an important role for the terminal complement activation products C5a and/or the MAC in warm myocardial IRI (30)(31)(32)(33). More recently, it has been shown that myocardial IRI in a nontransplant setting is dependent on IgM and the lectin pathway (34), and mice deficient in the classical or alternative pathway are not protected from myocardial IRI (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Targeted Complement Inhibitors Protect against Posttransplant Cardiac Ischemia and Reperfusion Injury and Reveal an Important Role for the Alternative Pathway of Complement Activation

Atkinson

Morris

et al. 2010

The Journal of Immunology

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Ischemia reperfusion injury (IRI) is an unavoidable event during solid organ transplantation and is a major contributor to early graft dysfunction and subsequent graft immunogenicity. In a therapeutic paradigm using targeted complement inhibitors, we investigated the role of complement, and specifically the alternative pathway of complement, in IRI to heart isografts. Mouse heterotopic isograft heart transplants were performed in C57BL/6 mice treated with a single injection of either CR2-Crry (inhibits all complement pathways) or CR2-fH (inhibits alternative complement pathway) immediately posttransplantation. Transplanted hearts were harvested at 12 and 48 h for analysis. Both inhibitors resulted in a significant reduction in myocardial IRI, as measured by histology and serum cardiac troponin I levels. Furthermore, compared with untreated controls, both inhibitors reduced graft complement deposition, neutrophil and macrophage infiltration, adhesion molecule expression (P-selectin, E-selectin, and I-CAM-1), and proinflammatory cytokine expression (TNF-α, IL-1β, KC, and MCP-1). The reduction in myocardial damage and cellular infiltration was not significantly different between CR2-Crry– and CR2-fH–treated mice, although adhesion molecule and cytokine levels were significantly lower in CR2-Crry–treated mice compared with CR2-fH–treated mice. In conclusion, the alternative complement pathway plays a major contributing role in myocardial IRI after heart transplantation, and local (targeted) complement inhibition has the potential to provide an effective and safe therapeutic strategy to reduce graft injury. Although total complement blockade may be somewhat more efficacious in terms of reducing inflammation, specific blockade of the alternative pathway is likely to be less immunosuppressive in an already immunocompromised recipient.

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“…The particular role of the MAC (C5b-9) comes from evidence that rabbits deficient in the complement protein C6 have a reduced infarct size in cardiac ischemiareperfusion models compared with C6-sufficient rabbits. 25 It has traditionally been assumed that liver is the source of complement proteins that participate in these events. But we have recently shown that complement proteins are produced in several organs of the body, including brain and heart.…”

mentioning

confidence: 99%

Human Heart Generates Complement Proteins That Are Upregulated and Activated After Myocardial Infarction

Yasojima

Schwab

McGeer

et al. 1998

Circulation Research

142

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Abstract-In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction. (Circ Res. 1998;83:860-869.)Key Words: complement gene expression Ⅲ classical pathway Ⅲ postmortem delay Ⅲ immunohistochemistry Ⅲ Western blotting Ⅲ liver complement T here have been many reports on association of complement proteins with myocardial damage. These include human myocardial infarcts, 1-8 as well as damaged hearts in animal models of ischemia. 8 -16 Activation of both the classical and alternative complement pathways has been reported. 17,18 Evidence that such activation is not an epiphenomenon, but contributes to tissue injury, comes directly from postmortem examination of human heart in which the membrane attack complex (MAC, C5b-9) has been identified on damaged muscle fibers. 4,7,19 It comes indirectly from animal models in which ischemic myocardial damage is ameliorated by interference with complement activation. Intervention by administration of C1 esterase inhibitor, 18,20,21 antibodies to C5a, 22 and the soluble form of CR-1 23,24 has reduced myocardial damage. The particular role of the MAC (C5b-9) comes from evidence that rabbits deficient in the complement protein C6 have a reduced infarct size in cardiac ischemiareperfusion models compared with C6-sufficient rabbits. 25 It has traditionally been assumed that liver is the source of complement proteins that participate in these events. But we have recently shown that complement proteins are produced in several organs of the body, including brain and heart. We 26 have also shown that production of C3 and C9 mRNAs and their protein products is sharply upregulated in isolated rabbit heart after reperfusion injury, and that the production by heart in this circumstance substantially exceeds that of normal liver. In brain, we 27,28 have shown that all proteins of the classical complement pathway are produced by neurons, and that this production is upregulate...

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Influence of the terminal complement-complex on reperfusion injury, no-reflow and arrhythmias: a comparison between C6-competent and C6-deficient rabbits

Cited by 47 publications

References 0 publications

Novel Small Molecule Inhibitor of C1s Exerts Cardioprotective Effects in Ischemia-Reperfusion Injury in Rabbits

Novel Small Molecule Inhibitor of C1s Exerts Cardioprotective Effects in Ischemia-Reperfusion Injury in Rabbits

Targeted Complement Inhibitors Protect against Posttransplant Cardiac Ischemia and Reperfusion Injury and Reveal an Important Role for the Alternative Pathway of Complement Activation

Human Heart Generates Complement Proteins That Are Upregulated and Activated After Myocardial Infarction

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