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

Abstract

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.

C1 inhibitor-mediated myocardial protection from chronic intermittent hypoxia-induced injury

“…Chronic intermittent hypoxia/reoxygenation is characteristic of CIH, and several studies support the notion that complement activation is involved in the pathogenesis of hypoxia/reoxygenation injury, and that complement inhibition reduces the extent of injury (5,8,9). In support of this hypothesis, studies have demonstrated that the localization/deposition of complement components (such as C1q, C3, C4 and C5) occurs in hypoxic myocardium (10)(11)(12)(13).…”

Complement Factor C5a Mediates Renal Ischemia-Reperfusion Injury Independent from Neutrophils

“…In myocardial I/R models, recent work indicates that the mannose-binding lectin, as well as the classical activation pathway, plays a role in complement activation and subsequent organ damage (22,23). Regarding the precise pathway of complement activation upon renal I/R injury much remains to be resolved, however evidence is growing that activation of the complement system plays a crucial role in the pathogenesis of renal I/R injury (5).…”

Evidence That Complement Protein C1q Interacts with C-Reactive Protein through Its Globular Head Region

“…CRP has been shown to colocalize with complement in acute myocardial infarction (39) and together they have been demonstrated to be important mediators of the resulting tissue damage (2,36). Inhibition of the early phase of complement activation has been demonstrated in an animal model to have cardioprotective effects following ischemia/reperfusion injury (40), and using complement inhibition as a therapy is the subject of many studies (reviewed in Refs. 41 and 42).…”