Complement Activation and Inhibition in Myocardial Ischemia and Reperfusion Injury

Homeister, Jonathan W.; Lucchesi, Benedict R.

doi:10.1146/annurev.pa.34.040194.000313

Cited by 88 publications

(43 citation statements)

References 40 publications

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“…Infliximab exerts its effects by fixing complement in cells, 15 which in the heart is reported to lead to cardiac myocyte lysis. 21 Etanercept stabilizes TNF-␣ and hence leads to an accumulation of TNF-␣ in the peripheral circulation. 15 In comparison, the effects of pentoxifylline are to reduce the synthesis of TNF-␣ by blocking transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

Therapy of Ischemic Cardiomyopathy With the Immunomodulating Agent Pentoxifylline

et al. 2004

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Background-Inflammatory immune activation commonly occurs in heart failure and may perpetuate this syndrome. We sought to determine whether the immunomodulating agent pentoxifylline enhances left ventricular function in patients with ischemic cardiomyopathy. We also investigated the effect of therapy on levels of brain natriuretic peptide (NT-pro BNP), C-reactive protein (CRP), tumor necrosis factor-␣ (TNF-␣), and the marker of apoptosis, Fas/Apo-1. Methods and Results-In a single-center, prospective, randomized, double-blind, placebo-controlled study, 38 patients with ischemic cardiomyopathy received pentoxifylline 400 mg TID or placebo in addition to standard therapy. Clinical assessment, radionuclide ventriculography, echocardiography, and blood analyses were performed at baseline and after 6 months. There were no differences in baseline characteristics between the groups. Five patients died (4 in the placebo group). Pentoxifylline treatment resulted in an improvement in functional class (PϽ0.005) and an increase in systolic blood pressure (PϽ0.05) and left ventricular radionuclide ejection fraction (PϽ0.05) compared with the placebo-treated group. There were reductions in plasma concentrations of CRP, NT-pro BNP, TNF-␣, and Fas/Apo-1 in the pentoxifylline compared with the placebo-treated group. Conclusions-In patients with heart failure due to ischemic left ventricular dysfunction, the addition of pentoxifylline to standard therapy results in improvements in clinical status and radionuclide ejection fraction, which are accompanied by reductions in plasma markers of inflammation, prognosis, and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Therapy of Ischemic Cardiomyopathy With the Immunomodulating Agent Pentoxifylline

et al. 2004

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“…occurs predominantly, if not exclusively, by the alternative pathway (62). Complement upregulates expression of endothelial cell adhesion molecules (63). DCs covalently fix marked amounts of macrophage-derived C3, the most abundant complement protein in the circulation, on their surface (64).…”

Section: Figurementioning

confidence: 99%

Cellular pathophysiology of ischemic acute kidney injury

Bonventre¹,

Yang²

2011

J. Clin. Invest.

1,619

1,604

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“…C5b, the larger fragment, initiates the formation of the membrane attack complex (C5b-9) which results in the lysis of bacteria and other pathogens. Although complement has important functions in host defense, it also contributes to the pathology in many inflammatory diseases (1), in xenotransplant rejection (2), and in reperfusion injury (3). This has prompted a search for inhibitors that can control activation of C5.…”

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C5 Convertase of the Alternative Pathway of Complement

Rawal

Pangburn

1998

Journal of Biological Chemistry

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Although proteolytic activation of the complement protein C5 initiates important defensive and occasionally pathological inflammatory reactions, the enzymatic properties of the enzymes responsible for this cleavage have never been examined. We have studied the kinetic parameters of the C5 convertase of the alternative pathway of complement, either bound to a zymosan surface or in its monomeric soluble form. C5 convertase enzymatic activity was measured as a function of C5 concentration by quantitating production of C5b,6 under physiological conditions of temperature, pH, and ionic strength. The C5 convertases appeared to follow Michaelis-Menten kinetics and exhibited similar catalytic rate constants (k cat ). However, the surface-bound enzyme, ZymC3b,Bb had a K m (1.4 M) that was 17 times lower than that of the soluble monomeric form of the enzyme, C3b,Bb (K m ‫؍‬ 24 M). The k cat for the cell-bound enzyme, ZymC3b,Bb was 0.0048 s ؊1 and that for soluble C3b,Bb was 0.0110 s ؊1 . Both forms of the enzyme had a low turnover number at V max (0.23 to 0.68 C5/min/enzyme). Substituting Mg 2؉ for Ni 2؉ did not alter the kinetic parameters but lowered the half-life of the enzyme by 5-7-fold. The kinetic data presented demonstrate that the fluid phase C5 convertase, C3b,Bb, can cleave C5 without the aid of a second C3b molecule. The results also show that the greater enzymatic activity previously observed for the surface-bound C5 convertases is not due to higher catalytic efficiency but is solely due to higher affinity for the substrate C5. In blood, C5 concentrations are 3-4-fold below the K m determined for the surface-bound C5 convertase suggesting a direct correlation between the local C5 concentration and production of the anaphylatoxin C5a and the cytolytic C5b-9 complex.C5 convertases are serine proteases that cleave C5, the fifth component of complement. The cleavage of C5 is the last enzymatic step in the complement activation cascade resulting in the formation of two biologically important fragments, C5a and C5b.1 Both fragments play vital roles in killing microorganisms. C5a, the smaller fragment, is a potent chemotactic and spasmogenic anaphylatoxin. It mediates inflammatory responses by stimulating neutrophils and phagocytes. C5b, the larger fragment, initiates the formation of the membrane attack complex (C5b-9) which results in the lysis of bacteria and other pathogens. Although complement has important functions in host defense, it also contributes to the pathology in many inflammatory diseases (1), in xenotransplant rejection (2), and in reperfusion injury (3). This has prompted a search for inhibitors that can control activation of C5. Specific inhibition of C5 activation would preserve the immune clearance and opsonization functions of complement which depend on C3b, but it would prevent the generation of both C5a and C5b-9. Recent approaches in blocking complement activation include inhibitory anti-C5 antibodies (4), synthetic peptides (5, 6), synthetic protease inhibitors (7,8), soluble constructs of ...

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Complement Activation and Inhibition in Myocardial Ischemia and Reperfusion Injury

Cited by 88 publications

References 40 publications

Therapy of Ischemic Cardiomyopathy With the Immunomodulating Agent Pentoxifylline

Therapy of Ischemic Cardiomyopathy With the Immunomodulating Agent Pentoxifylline

Cellular pathophysiology of ischemic acute kidney injury

C5 Convertase of the Alternative Pathway of Complement

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