Serum Levels of Mannose-Binding Lectin and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

Keller, Tymen; Leuven, Sander I. van; Meuwese, Marijn C.; Wareham, Nicholas J.; Luben, Robert; Stroes, Erik S.G.; Hack, C. Erik; Levi, Marcel; Khaw, Kay‐Tee; Boekholdt, S. Matthijs

doi:10.1161/01.atv.0000240517.69201.77

Cited by 64 publications

(56 citation statements)

References 40 publications

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“…Several population-based studies, analyzing either MBL genotypes or resulting serum levels, suggest a role for MBL in cardiovascular disease (34,(52)(53)(54)(55)(56)(57)(58). However, the results are contradictory, suggesting either a proatherogenic or antiatherogenic role of MBL in cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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“…Several observations indicate that MBL and the lectin pathway of complement activation may play an important role in cardiovascular disease pathology (1)(2)(3)(4). In our studies of RA patients, we have found that high serum levels of MBL increase the risk of ischemic heart disease, including myocardial infarction, in patients with high levels of IgG-G0.…”

Section: Replymentioning

confidence: 53%

Mannose‐binding lectin and agalactosyl IgG and risk of ischemic heart disease in rheumatoid arthritis: Comment on the article by Troelsen et al

Leuven

Stroes

2007

Arthritis & Rheumatism

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“…21 Contrary to these findings but in agreement with our data in this study, a recent study in 964 seemingly healthy men did show an association of elevated MBL levels with coronary heart disease. 22 So how can we explain the adverse effect of high MBL levels on graft and patient survival in our study? The finding of superior graft survival after SKPT confirms our earlier report demonstrating superior allograft survival in recipients with low MBL levels after deceaseddonor renal transplantation.…”

Section: Discussionmentioning

confidence: 89%

Low Pretransplantation Mannose-Binding Lectin Levels Predict Superior Patient and Graft Survival after Simultaneous Pancreas-Kidney Transplantation

Berger

Roos

Mallat

et al. 2007

Journal of the American Society of Nephrology

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Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and renal failure. However, this procedure is characterized by a high rate of postoperative infections, acute rejection episodes, and cardiovascular mortality. The lectin pathway of complement activation contributes to cardiovascular disease in diabetes and may play an important role in inflammatory damage after organ transplantation. This study therefore sought to determine how mannosebinding lectin (MBL), a major recognition molecule of the lectin pathway of complement activation, influences outcome after SPKT. MBL serum levels were determined in 99 and MBL genotypes in 97 consecutive patients who received an SPKT from 1990 through 2000 and related to patient and graft survival. At 12 yr, cumulative death-censored kidney graft survival was 87.5% in patients with an MBL level Ͻ400 ng/ml and 74.8% in the group with MBL levels Ͼ400 ng/ml (P ϭ 0.021). Pancreas graft survival was significantly better in patients with low MBL levels (P ϭ 0.016). MBL levels Ͼ400 ng/ml were associated with a hazard ratio of 6.28 for patient death (95% confidence interval 1.8 to 20.3; P ϭ 0.003). Accordingly, survival was significantly better in recipients with MBL gene polymorphisms associated with low MBL levels. These findings identify MBL as a potential risk factor for graft and patient survival in SPKT. It is hypothesized that MBL contributes to the pathogenesis of inflammation-induced vascular damage both in the transplanted organs and in the recipient's native blood vessels.

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Serum Levels of Mannose-Binding Lectin and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

Cited by 64 publications

References 40 publications

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Mannose‐binding lectin and agalactosyl IgG and risk of ischemic heart disease in rheumatoid arthritis: Comment on the article by Troelsen et al

Low Pretransplantation Mannose-Binding Lectin Levels Predict Superior Patient and Graft Survival after Simultaneous Pancreas-Kidney Transplantation

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