Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection.
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 mm2, 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.
Peng
Siwei
S
Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Larsson
Annika
A
Wassberg
Erik
E
Gerwins
Pär
P
Thelin
Stefan
S
Fu
Xin
X
Westermark
Per
P
D000368:Aged; D000682:Amyloid / Q000378:metabolism*; D000784:Aortic Dissection / Q000378:metabolism / Q000473:pathology*; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology*; D017545:Aortic Aneurysm, Thoracic / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D002478:Cells, Cultured; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D008875:Middle Aged; D008894:Milk Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000473:pathology
D000682:Amyloid; D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins; D020778:Matrix Metalloproteinase 2