The Role of Midkine in Arteriogenesis, Involving Mechanosensing, Endothelial Cell Proliferation, and Vasodilation
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International Journal of Molecular Sciences Review The Role of Midkine in Arteriogenesis, Involving Mechanosensing, Endothelial Cell Proliferation, and Vasodilation Ludwig T. Weckbach 1,2,3, Klaus T. Preissner 4 and Elisabeth Deindl 3,* 1 Medizinische Klinik und Poliklinik I, Klinikum der Universität, LMU Munich, 81377 Munich, Germany; [email protected] 2 Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, 82152 Planegg-Martinsried, Germany 3 Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 81377 Munich, Germany 4 Institute of Biochemistry, Medical School, Justus-Liebig-University, 35392 Giessen, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-89-2180-76504 Received: 23 July 2018; Accepted: 22 August 2018; Published: 29 August 2018 Abstract: Mechanical forces in blood circulation such as shear stress play a predominant role in many physiological and pathophysiological processes related to vascular responses or vessel remodeling. Arteriogenesis, defined as the growth of pre-existing arterioles into functional collateral arteries compensating for stenosed or occluded arteries, is such a process. Midkine, a pleiotropic protein and growth factor, has originally been identified to orchestrate embryonic development. In the adult organism its expression is restricted to distinct tissues (including tumors), whereby midkine is strongly expressed in inflamed tissue and has been shown to promote inflammation. Recent investigations conferred midkine an important function in vascular remodeling and growth. In this review, we introduce the midkine gene and protein along with its cognate receptors, and highlight its role in inflammation and the vascular system with special emphasis on arteriogenesis, particularly focusing on shear stress-mediated vascular cell proliferation and vasodilatation. Keywords: midkine; nitric oxide synthases; VEGF; endothelial-cell proliferation; vasodilation; arteriogenesis; hypoxia; shear stress; reactive oxygen species; tumor 1. Introduction After the discovery of the cytokine midkine (MK) in 1988, its main function was believed to orchestrate embryonic development [1]. However, multiple studies during the last three decades clearly indicated a functional impact of MK on the adult organism as well. By far, most of the studies on MK addressed its role in malignant diseases and suggested a detrimental effect for the host [2–5]. A significant part of the literature on MK has shown its ability to promote inflammatory responses. Different mechanisms of how MK could reinforce acute or chronic inflammation have been proposed as well and will be partially reviewed here [6]. In addition, recent studies demonstrated that MK serves as a major regulator of angiogenesis and arteriogenesis during pathological conditions in the vascular system. In light of the fast-growing burden of cardiovascular diseases, which are predominantly associated with atherosclerosis and occlusive arterial disease, e.g., in the heart, interventional strategies to modulate arteriogenesis, i.e., the growth of pre-existing arteriolar connections bypassing an occluded artery, may become novel noninvasive treatment modalities for patients with ischemia-related Int. J. Mol. Sci. 2018, 19, 2559; doi:10.3390/ijms19092559 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 2559 2 of 18 pathologies. In this review, we will summarize the recent findings on the functional impact of MK on the vascular system with a special focus on arteriogenesis and vascular remodeling. 2. Midkine Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 2 of 17 2.1. MK Gene and Protein the functional impact of MK on the vascular system with a special focus on arteriogenesis and In 1988vascular Kadomatsu remodeling. and colleagues discovered MK in retinoic acid-differentiated mouse embryonic carcinoma cells, an experimental model to study the early steps of embryogenesis [1]. Expression of 2. Midkine MK was upregulated exclusively during the midgestation period in mouse embryogenesis [7]. This fact, together with2.1. MK a predominantGene and Protein expression of MK in the kidneys of adult organisms, finally led to the name mid-kineIn (mid-gestation,1988 Kadomatsu and ki-dney) colleagues [6, 7discovered]. The mouse MK inMK retinoic gene acid-differentiated is located on chromosomemouse 2, while theembryonic human gene, carcinoma consisting cells, an of experimental four coding model exons to withstudy seventhe early mRNA steps of isoforms embryogenesis [8], was [1]. identified on chromosomeExpression 11 [9of, 10MK]. Amongwas upregulated a retinoic exclusivel acid responsey during element the midgestation and a binding period sitein mouse for the product embryogenesis [7]. This fact, together with a predominant expression of MK in the kidneys of adult of the Wilmsorganisms, tumor-suppressor finally led to the gene name WT-1, mid-kine a hypoxia-responsive (mid-gestation, ki-dney) element[6,7]. The hasmouse been MK identifiedgene is in the promoter regionlocated on of chromosome the MK gene 2, while [11– the13 ].human gene, consisting of four coding exons with seven mRNA The humanisoforms MK [8], was protein—composed identified on chromosome of 121 11amino [9,10]. Among acids—is a retinoic a heparin-binding acid response element growth and a factor with a molecularbinding weight site offor 13 the kDa product consisting of the Wilms of two tumor-suppressor similar domains, gene anWT-1, N-terminal a hypoxia-responsive (amino acids 1–52) element has been identified in the promoter region of the MK gene [11–13]. and a C-terminalThe domainhuman MK (amino protein—composed acids 62–121), of 121 which amino are acids—is connected a heparin-binding by a hinge growth domain factor (amino acids 53–61) [14].with Each a molecular domain weight contains of 13 kDa three consisting antiparallel of two similarβ-strands domains, [14 ].an TenN-terminal cysteine (amino residues, acids 1– which are highly conserved52) and a C-terminal among different domain (amino species, acids form 62–121), five which disulfide are connected bonds by (two a hinge bonds domain in (amino the C-terminal domain andacids three 53–61) bonds [14]. Each in the domain N-terminal contains three domain), antiparallel building β-strands the [14]. structure Ten cysteine of the residues, domains which [14 ]. MK is are highly conserved among different species, form five disulfide bonds (two bonds in the C-terminal a positivelydomain charged and three protein bonds containing in the N-terminal two heparin-bindingdomain), building the clusters structure with of the a domains number [14]. of MK arginine and lysine residuesis a positively (cluster charged 1: K79, protein R81, co K102;ntaining cluster two heparin-bi 2: K86, K87,nding R89),clusters located with a number in the C-terminalof arginine domain (Figure1)[and6,14 lysine]. MK residues may interact(cluster 1: viaK79, its R81, positively K102; cluster charged 2: K86, heparin-bindingK87, R89), located insites the C-terminal with heparin-like glycosaminoglycansdomain (Figure of 1) endothelial [6,14]. MK may cells, interact enabling via its MK positively to be charged immobilized heparin-binding on the luminalsites with site of the heparin-like glycosaminoglycans of endothelial cells, enabling MK to be immobilized on the luminal vessel wallsite [15 of, 16the]. vessel wall [15,16]. Figure 1. Protein structure of midkine (MK). The protein consists of an N-terminal domain (red) and Figure 1. Protein structure of midkine (MK). The protein consists of an N-terminal domain (red) and a C-terminal domain (yellow), which are connected by a hinge region (white). The heparin-binding a C-terminaldomains, domain which (yellow), consist of whichbasic amino are connectedacids, are located by ain hinge the C-terminal region domain (white). (labeled The heparin-bindingin blue, domains, whichblue arrows). consist Adapted of basic from aminoWeckbach acids, et al. 2011 are located[6], with the in permission the C-terminal of the authors domain. (labeled in blue, blue arrows). Adapted from Weckbach et al., 2011 [6], with the permission of the authors. MK together with pleiotrophin (PTN) forms its own so-called MK family [17], which is structurally not related to any other protein family. Both proteins show a 50% sequence identity and MK together with pleiotrophin (PTN) forms its own so-called MK family [17], which is structurally not related to any other protein family. Both proteins show a 50% sequence identity and complete conservation of positions of all cysteine residues [18]. The heparin-binding sites are also conserved in MK and PTN with only one basic amino acid exchanged (K84 in MK, R84 in PTN) [19]. A phylogenetic Int. J. Mol. Sci. 2018, 19, 2559 3 of 18 analysis showed a high conservation of the MK protein among different species with an amino acid sequence identity between human and murine MK of 87% [20]. In zebrafish, a very popular and established experimental animal model organism for a variety of human diseases, two MK molecules, midkine-a and midkine-b, have been discovered and most likely represent gene duplicates [21]. Drosophila melanogaster expresses two proteins sharing similarities with MK and PTN, named miple-1 and miple-2. Both proteins predominantly resemble the C-terminal domain of MK [22]. 2.2. MK Receptors For MK, a wide variety of receptors have been identified (Table1), which are believed to function as receptor complexes [6].