Ultrastructural Distribution of 36-kD Microfibril-associated Glycoprotein (MAGP-36) in Human and Bovine Tissues

Toyoshima, Tetsuhiko; Yamashita, Kayoko; Furuichi, Hiromi; Shishibori, Tsuyoshi; Itano, Toshifumi; Kobayashi, Ryōji

doi:10.1177/002215549904700809

Cited by 34 publications

(41 citation statements)

References 24 publications

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“…MFAP 4 is a 29-kDa elastin-binding protein and plays a role in elastogenesis. 37 Furthermore, MFAP 4 has high sequence homology to the aortic aneurysm-associated protein-40, which has been found in human abdominal aortic aneurysm. 38 Although not much is known about MFAP 4, there are indications that it might play an important role in aneurysm formation.…”

Section: Discussionmentioning

confidence: 98%

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

et al. 2009

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Background-Marfan syndrome (MFS) is a heritable disorder of connective tissue, affecting principally skeletal, ocular, and cardiovascular systems. The most life-threatening manifestations are aortic aneurysm and dissection. We investigated changes in the proteome of aortic media in patients with and without MFS to gain insight into molecular mechanisms leading to aortic dilatation. Methods and Results-Aortic samples were collected from 46 patients. Twenty-two patients suffered from MFS, 9 patients had bicuspid aortic valve, and 15 patients without connective tissue disorder served as controls. Aortic media was isolated and its proteome was analyzed in 12 patients with the use of 2-dimensional difference gel electrophoresis and mass spectrometry. We found higher amounts of filamin A C-terminal fragment, calponin 1, vinculin, microfibrilassociated glycoprotein 4, and myosin-10 heavy chain in aortic media of MFS aneurysm samples than in controls.Regulation of filamin A C-terminal fragmentation was validated in all patient samples by immunoblotting. Cleavage of filamin A and the calpain substrate spectrin was increased in the MFS and bicuspid aortic valve groups. Extent of cleavage correlated positively with calpain 2 expression and negatively with the expression of its endogenous inhibitor calpastatin. Conclusions-Our observation demonstrates for the first time upregulation of the C-terminal fragment of filamin A in dilated aortic media of MFS and bicuspid aortic valve patients. In addition, our results present evidence that the cleavage of filamin A is highly likely the result of the protease calpain. Increased calpain activity might explain, at least in part, histological alterations in dilated aorta. Key Words: aneurysm Ⅲ aorta Ⅲ calpain Ⅲ Marfan syndrome Ⅲ proteomics M arfan syndrome (MFS) is a disorder of connective tissue caused by mutations in the fibrillin-1 gene (FBN-1) that may lead to abnormal regulation of transforming growth factor-␤ (TGF-␤) signaling. 1 Clinical manifestation implies principally the cardiovascular, skeletal, and ocular systems, and other systems such as skin, lung, and dura may also be affected. Cardiovascular defects involve dilatation of the ascending aortic root leading to aortic aneurysm and dissection, which are the main cause of morbidity and mortality in MFS, and mitral valve prolapse with or without regurgitation. 2 Clinical Perspective on p 991Molecular mechanisms of aneurysm formation and its treatment are the subject of intensive research. Three key proteins seem to directly contribute to aneurysm formation. First, defective fibrillin-1 is thought to alter targeting and sequestration of TGF-␤, leading to increased TGF-␤ activity. 1 Blocking TGF-␤ activity with antagonists such as TGF-␤-neutralizing antibodies prevents aneurysm formation in a mouse model of MFS. 3 Second, angiotensin II (Ang II) is upregulated in MFS. 4 Treatment of patients with Ang II type 1 (AT 1 ) receptor (AT 1 R) blocker or angiotensin-converting enzyme (ACE) inhibitors reduces progression of aortic d...

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Section: Discussionmentioning

confidence: 98%

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

et al. 2009

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“…Human MFAP4 has been localized to elastic fibers in a variety of elastic tissues, including aorta (23), skin (24), and lung (23,25). Immunogold electron microscopy studies have shown that MFAP4 localizes to elastin-associated microfibrils but not microfibrils away from the elastin bundle (24). Together, these observations suggest that MFAP4 may contribute to the elastic fiber assembly and/or maintenance.…”

Section: Mfap4 (Microfibrillar-associated Protein 4)mentioning

confidence: 91%

“…MAGP-36 has been found to bind elastin and collagen in a calcium-dependent manner and to co-localize with elastin microfibrils (21,22). Human MFAP4 has been localized to elastic fibers in a variety of elastic tissues, including aorta (23), skin (24), and lung (23,25). Immunogold electron microscopy studies have shown that MFAP4 localizes to elastin-associated microfibrils but not microfibrils away from the elastin bundle (24).…”

Section: Mfap4 (Microfibrillar-associated Protein 4)mentioning

confidence: 99%

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Pilecki

Holm

Schlosser

et al. 2016

Journal of Biological Chemistry

116

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MFAP4 (microfibrillar-associated protein 4) is an extracellular glycoprotein found in elastic fibers without a clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues Phe 241 and Ser 203 in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization.Elastic fibers are key extracellular matrix structural elements of connective tissues that undergo repeated stretch, such as large arteries and the lung (1). The fibers consist of two major components: an amorphous elastin core surrounded by a sheath of fibrillin-rich microfibrils (2). Elastin is a highly hydrophobic polymer of the soluble precursor tropoelastin (3). Tropoelastin is known to undergo a self-assembly process known as coacervation (4), often believed to be a first step in the process of elastic fiber maturation. Because of the high content of lysine residues within the tropoelastin sequence, its assembly into a polymeric form is stabilized by formation of desmosine crosslinks, catalyzed by the lysyl oxidase (LOX) 3 enzyme family (5).Microfibrils, the other major component of elastic fibers, provide the structural scaffold for the deposition of elastin globules. They consist primarily of fibrillin-1 and fibrillin-2, large glycoproteins with a high degree of homology (6). Apart from fibrillins, numerous accessory proteins have been shown to associate with microfibrils or elastin and promote formation of mature fibers, including fibulins and microfibril-associated glycoproteins (MAGPs) (7-10). The importance of proper elastogenesis has been underscored by gene deficiency studies: mice lacking elastin, LOX, or fibrillin-1 die shortly after birth because of vascular abnormalities (11-13).MFAP4 (microfibrillar-associated protein 4) is an extracellular matrix protein belonging to the fibrinogen-related domain (FReD) family. The family includes several proteins engaged in tissue homeostasis and innate immunity, such as FIBCD1 (fibrinogen C domain-containing 1), ficolins, and angiopoietins (14 -16). The crystal structure of the FReD of several family members has been solved (17-19). The ligand-binding site, designated S1, is described in all the proteins and is located in close proximity to the calcium-binding site. MFAP4 has been reported to form homodimeric structures that further oligomerize, but its definite oligomerization pattern has not been established (20).MFAP4 is conside...

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“…4 MFAP4, known as 36-kDa microfibril-associated glycoprotein (MAGP36) 5 in other species, was first identified as a protein with a resemblance to tenascin in its amino acid composition and localization to the ECM in arteries. [6][7][8][9][10] MAGP36 is known to interact directly with ECM fibers, including elastin, collagen, and calvasculin. [6][7][8]11 Moreover, MAGP36 was demonstrated to bind integrin receptors on human aortic SMCs in an RGD-dependent manner.…”

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confidence: 99%

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

Schlosser¹,

Pilecki²,

Hemstra³

et al. 2016

ATVB

101

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V ascular smooth muscle cell (VSMC) activation and phenotypic switching are critical for remodeling processes in vascular proliferative disorders, including intimal hyperplasia. Both the migratory and proliferative activities of VSMCs, as well as the interplay between the extracellular matrix (ECM) and integrin receptors essentially, contribute to neointimal hyperplasia and restrictive remodeling processes in the vessels.1 Among integrins, the particular role of integrin α V β 3 in the induction of VSMC responses has been shown both in vivo and in vitro.

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Ultrastructural Distribution of 36-kD Microfibril-associated Glycoprotein (MAGP-36) in Human and Bovine Tissues

Cited by 34 publications

References 24 publications

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

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