One of the most important therapeutic targets of current cardiology practice is to determine optimal strategies for the minimization of myocardial necrosis and optimization of cardiac repair following an acute myocardial infarction. We have developed a genetic animal model of heart failure (desmin deficiency) in which extensive cardiomyocyte death and an acute inflammatory reaction is observed early in animal's life. This reaction is gradually regressed and is followed by a remodelling phase, sharing similarities to acute myocardial infarction.
The purpose of this study was to investigate if modulation of inflammatory reaction could be critical for achieving effective cardiac repair and regeneration in the above animal model.Results
Genome-wide array analysis was conducted, and an essential number of complement system components were significantly up-regulated in the desmin null (des-/-) hearts, compared to wild type. Massive complement activation (deposition of activated C3) is observed (by immunofluorescence) in the myocardium of des-/- animals in areas of necrotic cells debris and acute inflammatory infiltrate. To further study the role of complement system in the above animal model we have eliminated three key components of complement cascade activation, the C3 the C5 and the C5a receptor (C5aR) genes. Increased (19%), cardiac tissue injury (infiltrating cells, fibrosis, calcification) and mortality are observed in double null animals for desmin and C3 (des-/- C3-/-), compared to des-/-. On the other hand considerable reduction of calcification and fibrosis is observed in desmin/C5 double null animals (30%) and in desmin/C5aR double null animals (22%). In addition improved cardiac function (Fraction Shortening) was observed in des-/-C5-/- (17%) and in des-/-C5aR (30%) double null mice compared to des-/-, as estimated by echocardiography. Also our results indicate that one of the ways by which inhibitors of the coagulation cascade could exert their beneficial effects, is by inhibiting complement system activation at the C5 level. The above results coincide with a role of C3 in eliminating apoptotic/necrotic cells with minimal destruction of the injured myocardium, and on the other hand with a proinflammatory role of C5 activation and of C5a anaphylatoxin generation.Conclusions
Complement system modulation attenuates cardiac tissue injury and adverse remodelling in a heart failure mouse model, and one of the ways by which inhibitors of the coagulation cascade could exert their beneficial effects in cardiology practice, is by inhibiting complement system activation.