The effect of C1 inhibitor on myocardial ischemia and reperfusion injury.
BACKGROUND
Activation of the complement system has been demonstrated to be an important mechanism in the mediation of myocardial ischemia and reperfusion (MIR) injury. C1 inhibitor (C1INH) has been shown to be beneficial in experimental MIR models. The underlying mechanism of this effect has been assumed to result primarily from inhibition of complement system activation. We recently demonstrated that C1INH plays a direct role in suppression of leukocyte transmigration in the mouse intestinal ischemia and reperfusion model. The purpose of this study was to investigate the mechanism of the beneficial effect of C1INH in mouse MIR model.


METHODS
C57BL/6, C1INH-deficient (C1INH(-/-)), and C3-deficient mice (C3(-/-)) were subjected to 30-min (C57BL/6 and C1INH(-/-)) or 60-min (C3(-/-)) occlusion of the left anterior descending branch of the coronary artery followed by 4-h reperfusion. C1INH or reactive center cleaved inactive C1INH (iC1INH) was injected intravenously 5 min before reperfusion.


RESULTS
Myocardial infarct size relative to the area at risk or relative to left ventricular area was significantly reduced in C1INH-treated wild-type, C1INH(-/-), and C3(-/-) mice compared with vehicle-treated mice. MIR induced an increase in myocardial polymorphonuclear neutrophil accumulation and plasma cardiac specific troponin I levels in vehicle-treated MIR mice, while C1INH treatment significantly attenuated these effects. iC1INH had a similar protective effect.


CONCLUSIONS
These results suggested that C1INH prevented MIR injury in mice and that this cardioprotective effect may not solely result from complement inhibition, but might be also contributed by inhibiting leukocyte recruitment into ischemic tissue, an effect that is not mediated via protease inhibition.
Immune Disease Institute, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USA. fengxinlu@gmail.com
Fengxin
F
Lu
Stacey M
SM
Fernandes
Alvin E
AE
Davis
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D019210:Troponin I / Q000097:blood
D015415:Biomarkers; D050718:Complement C1 Inhibitor Protein; D003176:Complement C3; C487284:Serping1 protein, mouse; D019210:Troponin I