Abstract 12608: Detrimental Role of Complement After Myocardial Infarction
Complement contributes to tissue injury after ischemia/reperfusion injury. Activation of the complement system converges on the activation of complement factor C3. C3 is produced in the myocardium early after cardiac injury indicating a detrimental role of the complement system in heart failure. However, the expression and function of complement has not been defined yet. In the failing mouse heart, C3 was activated (immunohistochemistry week 1 and week 8). Following coronary artery ligation, C3 knockout (KO) exhibited significantly reduced left ventricular dilatation over 3 weeks compared to wildtype (WT) controls (endsystolic diameters by transthoracic echocardiography, WT vs. KO, 4.6±0.2 mm vs. 5.4±0.3 mm, p=0.04). Infiltration of inflammatory cells, collagen content as well as the rate of apoptosis (WT vs. KO, 7.0±1.5 vs. 1.6±0.7%, p=0.01) were significantly lower in the KO mice after myocardial infarction (MI). This indicates that complement has a detrimental role after MI. C3 can be activated by the classical (antigen-antibody reaction), MBL (mannose binding lectine) or alternate pathways. Thus, we performed MI in Rag1 KO (lack of B−/ T-cells and antibodies) and MBL KO mice: Rag1 as well as MBL KO mice displayed significantly exaggerated left ventricular dilatation after MI; C3 complement deposition was still detectable in Rag1 and MBL KOs. Thus, C3 activation in ischemia is likely to be mediated by the alternate pathway. Downstream of C3, complement factor C5 is activated leading to the formation of membrane attack complex (MAC) which causes lysis of cells. Yet, C5 KO mice were not protected since there was no difference in mortality and left ventricular remodelling after MI. However, left ventricular remodeling was significantly improved in mice lacking the C3a receptor (endsystolic diameters by transthoracic echocardiography, WT vs. KO, 6.1±0.3 mm vs. 5.3±0.2 mm, p=0.03). In conclusion, by testing C3/ Rag1/ MBL/ C5/ C3aR KO after myocardial infarction, we found the complement factor C3 to be activated by the alternate pathway after MI. Absence of C3 reduces left ventricular dilatation after MI through the C3a receptor, but not through C5. The C3a receptor might therefore be an attractive target to prevent cardiac remodeling and heart failure.
- © 2010 by American Heart Association, Inc.