Medin: An integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid

Häggqvist, Bo; Näslund, Jan; Sletten, Knut; Westermark, Gunilla T.; Mucchiano, Gerd; Tjernberg, Lars O.; Nordstedt, Christer; Engström, Ulla; Westermark, Per

doi:10.1073/pnas.96.15.8669

Cited by 196 publications

(166 citation statements)

References 40 publications

Supporting

Mentioning

161

Contrasting

Order By: Relevance

“…A majority of the samples, including the control materials, contained amyloid in the extracellular matrix of the media. The deposits had the characteristics of medin-derived amyloid, 11,35 with small widely spread aggregates. Amyloid was often, but not always, observed as thin bands closely connected to the elastic laminae (Figure 1c and d).…”

Section: Histological Findingsmentioning

confidence: 99%

“…9,10 The main amyloid fibril protein is medin (or AMed), which is a 50 amino-acid residue internal cleavage product of the precursor protein lactadherin. 11 Lactadherin is a 364 amino-acid residue protein found in many tissues [11][12][13][14] and has many proposed functions. 13,[15][16][17] To these functions we have added the ability of lactadherin to bind to elastin, and we have suggested that lactadherin acts as a linker between smooth muscle cells and elastin through its RGD-sequence at the N-terminal part and its medin part close to the C terminus.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection

Peng

Larsson

Wassberg

et al. 2007

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

The pathogenesis of sporadic thoracic aortic aneurysm and dissection, which may lead to rupture of the aorta, remains largely unknown. Amyloid deposits, formed from the medin peptide, are very prevalent in the media of the thoracic aorta. We have studied the occurrence of medin-derived amyloid in specimens from patients with thoracic aortic aneurysm, aortic dissection type A and normal dimensioned aorta. Surprisingly, the amount of amyloid was significantly lower in the aneurysm and dissection groups (0.63±0.13 and 0.36±0.24 amyloid particles per mm 2 , respectively) compared to the control material (2.37 ± 0.58). However, focal medin immunoreactivity not associated with amyloid was found more conspicuously in the media of the two diseased groups. Recent amyloid research indicates that prefibrillar oligomeric aggregates, rather than mature amyloid fibrils, are toxic to the surrounding cells. The non-amyloid medin immunoreactivity observed may represent such toxic oligomers. This is supported by the fact that aggregated medin induced death of aortic smooth muscle cells in vitro. In addition, cells incubated together with medin increased the production of matrix metalloproteinase-2, a protease that degrades elastin and collagen and subsequently weakens the vessel wall. We therefore propose that medin oligomers are involved in the degeneration process of sporadic thoracic aortic aneurysm and dissection.

show abstract

Section: Histological Findingsmentioning

confidence: 99%

mentioning

confidence: 99%

Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection

Peng

Larsson

Wassberg

et al. 2007

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Nucleus formation requires a series of association steps of monomers, which are thermodynamically unfavorable, representing the rate-limiting step in amyloid fibril formation in vitro. Once the nucleus (n-mer) has been formed, further addition of monomers becomes thermodynamically favorable, resulting in rapid extension of amyloid fibrils in vitro.Many amyloidogenic proteins carry key regions that are specific to each amyloid protein (7,(27)(28)(29)(30). For an example, a 10-residue peptide of transthyretin can make fibrils that exhibit characteristics typical of the intact (127-amino acid residues) transthyretin (7).…”

mentioning

confidence: 99%

“…Many amyloidogenic proteins carry key regions that are specific to each amyloid protein (7,(27)(28)(29)(30). For an example, a 10-residue peptide of transthyretin can make fibrils that exhibit characteristics typical of the intact (127-amino acid residues) transthyretin (7).…”

mentioning

confidence: 99%

“…For an example, a 10-residue peptide of transthyretin can make fibrils that exhibit characteristics typical of the intact (127-amino acid residues) transthyretin (7). In the case of medin, responsible for aortic medial amyloid, the most common human amyloid, the C-terminal 8-residue peptide, can form the amyloid fibrils (27). Identifying such a key region provides a clue to understanding the mechanism of amyloid fibril formation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Investigation of a Peptide Responsible for Amyloid Fibril Formation of β2-Microglobulin byAchromobacter Protease I

Kozhukh¹,

Hagihara²,

Kawakami³

et al. 2002

Journal of Biological Chemistry

119

141

View full text Add to dashboard Cite

To obtain insight into the mechanism of amyloid fibril formation from ␤ 2 -microglobulin (␤2-m), we prepared a series of peptide fragments using a lysine-specific protease from Achromobacter lyticus and examined their ability to form amyloid fibrils at pH 2.5. Among the nine peptides prepared by the digestion, the peptide Ser 20 -Lys 41 (K3) spontaneously formed amyloid fibrils, confirmed by thioflavin T binding and electron microscopy. The fibrils composed of K3 peptide induced fibril formation of intact ␤2-m with a lag phase, distinct from the extension reaction without a lag phase observed for intact ␤2-m seeds. Fibril formation of K3 peptide with intact ␤2-m seeds also exhibited a lag phase. On the other hand, the extension reaction of K3 peptide with the K3 seeds occurred without a lag phase. At neutral pH, the fibrils composed of either intact ␤2-m or K3 peptide spontaneously depolymerized. Intriguingly, the depolymerization of K3 fibrils was faster than that of intact ␤2-m fibrils. These results indicated that, although K3 peptide can form fibrils by itself more readily than intact ␤2-m, the K3 fibrils are less stable than the intact ␤2-m fibrils, suggesting a close relation between the free energy barrier of amyloid fibril formation and its stability.Many proteins and peptides form amyloid fibrils (1-3). Although most are related to diseases, it has been shown that several proteins (4, 5) and peptides (6, 7) that are not related to disease can also form amyloid fibrils. Amyloid fibril formation is now recognized as a phenomenon common to many proteins. On the other hand, amyloid fibrils are homogeneous, and it is rarely possible to form chimeric fibrils composed of distinct amyloid proteins or peptides (8,9). This high species barrier suggests that the amyloid fibrils are stabilized by specific interactions of amyloid proteins, which are governed by the characteristic primary and higher order structures of each amyloid protein. Thus, amyloid fibrils can be considered to be alternatively folded conformations of globular proteins, and understanding of their properties is essential to obtain further insight into the mechanism of protein folding.␤ 2 -Microglobulin (␤2-m) 1 -related amyloidosis is a common and serious complication in patients on long term hemodialysis (10 -12). Carpal tunnel syndrome and destructive arthropathy associated with cystic bone lesions are the major clinical manifestations of ␤2-m-related amyloidosis (13). Although ␤2-m, the light chain of the type I major histocompatibility complex (14, 15), was identified as a major structural component of amyloid fibrils deposited in the synovia of the carpal tunnel (10), the mechanism of amyloid fibril formation by ␤2-m is still unknown (16,17,25,26). Naiki and co-workers (18 -20) have been studying the amyloid fibril formation of ␤2-m as well as other amyloid fibrils (21-24). They established a kinetic experimental system to analyze amyloid fibril formation in vitro, in which the extension phase with the seed fibrils is quantitatively characte...

show abstract

Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta

et al. 2001

Self Cite

View full text Add to dashboard Cite

Previous studies have shown that the amyloid localized to the aortic intima may be a biochemical entity different from other forms of localized amyloid. The amyloid fibril protein in one patient studied consisted of an N-terminal fragment of apolipoprotein A-1 (apo A-1). Since this patient was later shown to carry a missense mutation in the apo A-1 gene, leading to a deletion at position 107 of the mature protein, the question remained whether wild-type apo A-1 is amyloidogenic. In autopsy specimens from the thoracic aorta from 69 individuals, intimal atherosclerotic plaque-related amyloid was present in 11 cases (16%) and amyloid outside plaques in 37 cases (54%). The immunoreactivity of amyloid localized to the aortic intima was evaluated with the aid of antisera against N-terminal segments of apo A-1. The amyloid in association with atherosclerotic plaques was positively labelled by immunohistochemistry. The amyloid fibril protein from one patient, previously shown not to carry any mutation in the apo A-1 gene, was purified and shown by amino acid sequence analysis to be of apo A-1 nature. The result shows that wild-type apo A-1 is amyloidogenic and gives rise to a common localized form of amyloid associated with atherosclerosis.

show abstract

Medin: An integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid

Cited by 196 publications

References 40 publications

Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection

Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection

Investigation of a Peptide Responsible for Amyloid Fibril Formation of β2-Microglobulin byAchromobacter Protease I

Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta

Contact Info

Product

Resources

About