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Mannan-Binding Lectin in Cardiovascular Disease Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 616817, 13 pages http://dx.doi.org/10.1155/2014/616817 Review Article Mannan-Binding Lectin in Cardiovascular Disease Izabela Pdgowska-Klimek1 and Maciej CedzyNski2 1 Department of Anesthesiology and Intensive Care, Polish Mother’s Memorial Hospital Institute, Rzgowska 281/289, 93-338 Łod´ z,´ Poland 2 Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łod´ z,´ Poland Correspondence should be addressed to Izabela Pągowska-Klimek; [email protected] Received 27 January 2014; Accepted 10 April 2014; Published 30 April 2014 Academic Editor: Robert M. Starke Copyright © 2014 I. Pągowska-Klimek and M. Cedzynski.´ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cardiovascular disease remains the leading cause of mortality and morbidity worldwide so research continues into underlying mechanisms. Since innate immunity and its potent component mannan-binding lectin have been proven to play an important role in the inflammatory response during infection and ischaemia-reperfusion injury, attention has been paid to its role in the development of cardiovascular complications as well. This review provides a general outline of the structure and genetic polymorphism of MBL and its role in inflammation/tissue injury with emphasis on associations with cardiovascular disease. MBL appears to be involved in the pathogenesis of atherosclerosis and, in consequence, coronary artery disease and also inflammation and tissue injury after myocardial infarction and heart transplantation. The relationship between MBL and disease is rather complex and depends on different genetic and environmental factors. That could be why the data obtained from animal and clinical studies are sometimes contradictory proving not for the first time that innate immunity is a “double-edge sword,”sometimes beneficial and, at other times disastrous for the host. 1. Mannan-Binding Lectin: An Overview of serine proteases (MASPs), the ability to activate complement Structure and Synthesis via the lectin pathway. Mannan-binding lectin belongs to the collectin family, a Historically,innateimmunitywasidentifiedasthefirst- group of C-type lectins also possessing a collagen-like helical line defense system, protecting an organism from invad- domain. Human MBL exists as a series of oligomers of 2– ing pathogens and abnormal self-derived components. Its 6 subunits, built up from three identical polypeptide chains immediate response prevents the spreading of progressive (24 kDa, 228 amino acids each). The apparent molecular systemic infection after contact with pathogens. Further- weights of these oligomers range from approx. 150,000 to more, it takes part in the clearance of damaged cells and approx. 450,000, taking into account glycosylation. It forms tissues, preventing the development of chronic inflammation, a “bouquet-like” structure. MBL, like other collectins, is cancer, or uncontrolled autoimmune responses. There are characterized by the presence of four regions. (1) The short N- two phases of the innate immune response: recognition and terminal cysteine-rich domain is responsible for the arrange- elimination of targets. The innate immunity system functions ment of subunits in the oligomer, dependent on disulphide via a network of cellular and humoral factors. Mannan- bonds; this region consists of 21 amino acids, including binding lectin (MBL), also known as mannose-binding lectin three Cys residues. (2) The collagen-like region interacts with or mannan- (mannose-) binding protein (MBP), is a soluble MASPs; it consists of 59 amino acids (among them 19 Gly- (humoral) pattern-recognition molecule thought to be an X-Y triplets); this domain is glycosylated. (3) Next, an - important component of the innate immune system. MBL helical “neck” region (30 amino acids) stabilizes polypep- has opsonic activity and, in cooperation with MBL-associated tide chains within a structural subunit. (4) The C-terminal 2 BioMed Research International carbohydrate-recognition domain (CRD) is responsible for binding of the MBL-MASP complex to the target structure, pattern recognition and consists of 118 amino acids [1–6]. conformational changes lead to the activation of MASPs MBL binds with the highest affinity to D-mannose, N-acetyl- which in consequence makes the cleavage of C4 and C2 D-glucosamine, and L-fucose which allows the specific recog- possible and thus the initiation of the complement cascade. nition of numerous polysaccharides and glycoconjugates In spite of the different initiation mechanism, the lectin like bacterial lipopolysaccharides, capsular polysaccharides, pathway resembles the classical pathway (CP), forming the fungal mannans, and so forth. It moreover recognizes some same convertases for C3 and C5 components. Within the phospholipids, Neisseria outer membrane proteins, and DNA MASP family, three proteases (MASP-1, MASP-2, and MASP- of apoptotic cells [7–9]. Mannan-binding lectin is synthesized 3) and two related, nonenzymatic proteins, MAp19 (sMAP) by hepatocytes and secreted into the blood in an oligomeric and MAp44 (MAP-1), have been identified. MASP-1, MASP- form. Moreover, specific mRNA has been found in bone 3, and MAp44 are the products of alternative splicing of the marrow,fetallung,smallintestine,andtestis[10]. Its synthesis MASP1/3 gene while MASP-2 and MAp19 are synthesized is controlled by the MBL2 gene, located on chromosome 10 under the control of the MASP2 gene [4, 19–21]. (10q11.2) and regulated in a similar manner to acute phase proteins. The plasma concentration of MBL can increase up MASP-2 is believed to be the key enzyme responsible for to 3-fold in response to infection. In healthy individuals, an LP activation as its proteolytic activity against C4 and C2 average plasma (serum) level is approx. 1 g/mL; however significantly exceeds the activity of C1s, the corresponding it ranges from <0.1 g/mL up to >5 g/mL. The MBL2 gene element of the classical pathway [4, 19, 22]. MASP-1 was contains 4 exons and 3 introns. Most mammals (but not believed to upregulate lectin pathway activation. However, humans or chimpanzees) synthesize two MBL forms: A and recently, its crucial role in MASP-2 activation has been C. Human MBL resembles the C form. The MBL1 pseudogene postulated [23–25]. MASP-3 and nonenzymatic proteins are (not expressed), corresponding to the A form, has been found believedtoplayaregulatoryroleinthisprocess[19, 26–28]. A in the human genome. Exon 1 of the MBL2 gene encodes schematicoverviewofLPactivationispresentedinFigure 1. the signal peptide, the cysteine-rich domain, and part of the collagen-like region. Exon 2 encodes the remaining part of the latter. Exon 3 encodes the neck region while exon 4 3. Involvement of MBL-Associated encodes the CRD [3–6, 11, 12]. Serine Proteases in Coagulation and MBL deficiency, believed to be the most common human Kallikrein-Kinin Systems immunodeficiency, markedly depends on MBL2 gene point mutations in codons 52, 54, and 57 of exon 1. These variants, The increased infection susceptibility of MBL-deficient indi- giving dominant alleles D, B, and C, respectively (commonly vidualsisnowwelldocumentedbynumerouslaboratory designated collectively as O; the wild-type is designated as and clinical data but its description is outside the scope of A), lead to disruption of the collagen domain structure. This, this review. Recent studies bring an increasing amount of in consequence, prevents oligomerization of the basic triplet evidence that MBL plays an important role in other systemic polypeptide subunit (and therefore normal interaction with processes including coagulation, inflammation, and tissue MASPs) resulting in diminished complement activation and injury. opsonic activity [6, 13–15]. MASP-1 and -2 may participate in activation of the A shortened biological half-life of the protein is a reflec- coagulation system. The former is able to cleave fibrinogen, tion of increased sensitivity to serum metalloproteases [16]. factor XIII, and thrombin-activatable fibrinolysis inhibitor As well as the aforementioned mutations, polymorphisms in (TAFI) [29–34] while MASP-2 is able to cleave prothrom- the promoter region (at positions –550 and –221; variants bin [32]. Moreover, Megyeri et al. [35]foundMASP-1to H/L and Y/X, resp.) and the untranslated region of exon 1 +4 interact with protease-activated receptor-4, a mediator of (at position , variants P/Q) have been described. The first inflammation and platelet activation. Later, Doboetal.[´ 36] two (and possibly the third) influence gene expression and, found high-molecular-weight kininogen to be its additional in consequence, the serum concentration of the protein. The substrate. This activity (like that of kallikrein) enables release highest MBL level occurs in association with promoter geno- type HYP/HYP, and the lowest with LXP/LXP homozygotes of bradykinin, a highly proinflammatory mediator of the [6, 13–15]. kinin-kallikrein system. Although MASP-2 cleaves kininogen as well, no bradykinin is released during this process [36]. The contribution of MASPs to fibrin clot formation 2. MBL-Dependent Complement Activation on the surface of pathogens may limit dissemination of Until recently, MBL was believed to be the sole collectin infection [32]. The involvement
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