MASP-2 activation is involved in ischemia-related necrotic myocardial injury in humans

Zhang, Ming; Hou, Yunfang Joan; Çavuşoğlu, Erdal; Lee, Daniel; Steffensen, Rudi; Yang, Liming; Bashari, Daniel R.; Villamil, Jose; Moussa, Motaz; Fernaine, George; Jensenius, Jens Christian; Marmur, Jonathan D.; Ko, Wilson; Shevde, Ketan

doi:10.1016/j.ijcard.2011.11.032

Cited by 28 publications

(32 citation statements)

References 46 publications

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“…Peripheral blood cTnI levels increased significantly following cardiac surgery compared with the immediate pre-surgery values (Table 2), consistent with previous literature [7, 8, 81]. A univariate analysis showed that coronary Bb levels immediately after release of AXCL directly correlated with post-surgical peripheral blood cTnI levels (Spearman’s rho correlation coefficient = 0.465, P < 0.01; Fig 5a).…”

Section: Resultssupporting

confidence: 89%

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

et al. 2017

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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.

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Section: Resultssupporting

confidence: 89%

“…The lectin pathway can recognize these antibody-neoantigen complexes and appears to be the dominant pathway of C3 activation [73, 81, 105]. C3 activation is then amplified in a fB-alternative pathway-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…In another study, 29 patients with acute MI had significantly lower MASP-2 levels compared with 50 healthy individuals, or 27 patients with coronary artery disease (CAD) but without acute MI [33]. Lower MASP-2 levels were also found in 81 patients after cardiac surgery with cardiopulmonary bypass compared with before surgery, and it was suggested that reduction of MASP-2 levels was caused by complement activation during myocardial ischaemia [33]. In a study in 135 patients with acute stroke, MASP-2 levels were measured on days 0-4, 7 and 90, but showed neither any significant changes over time, differences between ischaemic (n = 109) and haemorrhagic stroke (n = 26), nor any association with clinical outcome [34].…”

Section: Introductionmentioning

confidence: 96%

“…These patients had significantly lower MASP-2 levels at admission compared with 256 patients without cardiovascular events, but after adjustment for risk factors MASP-2 was not an independent predictor of cardiovascular events [32]. In another study, 29 patients with acute MI had significantly lower MASP-2 levels compared with 50 healthy individuals, or 27 patients with coronary artery disease (CAD) but without acute MI [33]. Lower MASP-2 levels were also found in 81 patients after cardiac surgery with cardiopulmonary bypass compared with before surgery, and it was suggested that reduction of MASP-2 levels was caused by complement activation during myocardial ischaemia [33].…”

Section: Introductionmentioning

confidence: 98%

Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases

Frauenknecht

Thiel

Storm

et al. 2013

Clinical and Experimental Immunology

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SummaryGrowing evidence suggests a prominent role of the complement system in the pathogenesis of cardio-and cerebrovascular diseases (CVD). Mannanbinding lectin-associated serine proteases (MASPs) MASP-1 and MASP-2 of the complement lectin pathway contribute to clot formation and may represent an important link between inflammation and thrombosis. MBLassociated protein MAp44 has shown cardioprotective effects in murine models. However, MAp44 has never been measured in patients with CVD and data on MASP levels in CVD are scarce. Our aim was to investigate for the first time plasma levels of MAp44 and MASP-1, -2, -3 concomitantly in patients with CVD. We performed a pilot study in 50 healthy volunteers, in stable coronary artery disease (CAD) patients with one-vessel (n = 51) or three-vessel disease (n = 53) and age-matched controls with normal coronary arteries (n = 53), 49 patients after myocardial infarction (MI) and 66 patients with acute ischaemic stroke. We measured MAp44 and MASP-1 levels by in-house time-resolved immunofluorometric assays. MASP-2 and MASP-3 levels were measured using commercial enzyme-linked immunosorbent assay kits. MASP-1 levels were highest in subacute MI patients and lowest in acute stroke patients. MASP-2 levels were lower in MI and stroke patients compared with controls and CAD patients. MASP-3 and MAp44 levels did not differ between groups. MASP or MAp44 levels were not associated with severity of disease. MASP and MAp44 levels were associated with cardiovascular risk factors including dyslipidaemia, obesity and hypertension. Our results suggest that MASP levels may be altered in vascular diseases. Larger studies are needed to confirm our results and elucidate the underlying mechanisms.

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“…In a cohort study of individuals with T2DM, MASP-2 levels were significantly decreased in patients with acute cardiovascular events (Mellbin et al, 2012). MASP-2 levels were also lower in another study in patients with acute MI (Zhang et al, 2013). These first data suggest that MASP-1 and MASP-2, both of which interact with coagulation, are altered in patients with acute cardio-and cerebrovascular diseases.…”

Section: Masps In Cardiovascular Diseasesmentioning

confidence: 82%

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

Dobó

Schroeder

Jenny

et al. 2014

Molecular Immunology

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MASP-1 is a versatile serine protease that cleaves a number of substrates in human blood. In recent years it became evident that besides playing a crucial role in complement activation MASP-1 also triggers other cascade systems and even cells to mount a more powerful innate immune response. In this review we summarize the latest discoveries about the diverse functions of this multi-faceted protease. Recent studies revealed that among MBLassociated serine proteases, MASP-1 is the one responsible for triggering the lectin pathway via its ability to rapidly autoactivate then cleave MASP-2, and possibly MASP-3. The crystal structure of MASP-1 explains its more relaxed substrate specificity compared to the related complement enzymes. Due to the relaxed specificity, MASP-1 interacts with the coagulation cascade and the kinin generating system, and it can also activate endothelial cells eliciting pro-inflammatory signaling.

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MASP-2 activation is involved in ischemia-related necrotic myocardial injury in humans

Cited by 28 publications

References 46 publications

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

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

Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

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