Activation of Complement Factor B Contributes to Murine and Human Myocardial Ischemia/Reperfusion Injury

Abstract

The pathophysiology of myocardial injury resulting from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT mice, a manipulation that resulted in marked myocardial necrosis associated with upregulated myocardial expression of fB gene, activation of fB protein, and myocardial deposition of C3 activation products. In contrast, in fB−/− mice, the same procedure resulted in significantly reduced myocardial necrosis and diminished deposition of C3 activation products in the myocardial tissue. To extend the analysis to humans we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, the levels were directly related to the length of the AXCL and correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis. Taken together, our results support the conclusion that fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.