Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury

Abstract

The pathophysiology of myocardial injury that results 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 C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with 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 (% ventricular tissue necrotic; fB-/- mice, 20 ± 4%; WT mice, 45 ± 3%; P < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB-/- mice, 0 ± 0%; WT mice, 31 ± 6%; P<0.05). Reconstitution of fB-/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies 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, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating 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.

Non-Invasive whole-body detection of complement activation using radionuclide imaging in a mouse model of myocardial ischaemia-reperfusion injury

“…Studies in other models of inflammatory and immune disease have shown close correlation between the accumulation of C3d, the duration of ischaemia and tissue infarction 5 , 6 . Moreover, there are numerous pre-clinical and clinical studies that demonstrated involvement of Complement and in particular C3d in myocardial reperfusion injury 8 – 11 . As a clinical assay, complement measurement in blood, urine and tissue biopsy samples is widely used as a biomarker for many clinical conditions 12 .…”

Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation

“…Numerous studies have shown that the complement system is an important participant in the pathophysiological process of myocardial I/R injury 6,17,18 . Conversely, inhibiting complement system activation can significantly reduce myocardial I/R injury and myocardial infarct size [19][20][21] .…”

“…In response to myocardial injury, the complement cascade is activated and initiates an inflammatory response involving the recruitment of polymorphonuclear leukocytes and the release of inflammatory cytokines. Indeed, the excessive activation of the complement and its products C3 and C5a play an important role in myocardial necrosis during myocardial I/R 5,6 . Moreover, the generation of the anaphylatoxins C3 and C5a further activates the c-Jun N-terminal kinase (JNK) signaling to aggravate inflammatory response 7 .…”

The role of the complement factor B‒arginase‒polyamine molecular axis in uremia‐induced cardiac remodeling in mice

“…Chun et al. also reported that complement factor B (CFB) from circulation contributed to myocardial necrosis in ischemia/reperfusion‐treated mice and its deficiency would remarkably limit the injury . It is well known that cardiac remodeling (CR), in which immunological factors play a key role, is the pathological basis of heart failure in patients with ESRD .…”

“…Coan et al discovered that Cfb −/− rats manifested lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass [16]. Chun et al also reported that complement factor B (CFB) from circulation contributed to myocardial necrosis in ischemia/reperfusion-treated mice and its deficiency would remarkably limit the injury [17]. It is well known that cardiac remodeling (CR), in which immunological factors play a key role, is the pathological basis of heart failure in patients with ESRD [18].…”