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

Aortic medial amyloid is a form of localized amyloid that occurs in virtual ly all individuals older than 60 years, The importance and impact of the am yloid deposits are unknown. In this study we have purified a 5.5-kDa aortic medial amyloid component, by size-exclusion chromatography and RP-HPLC, fr om three individuals, and we have shown by amino acid sequence analysis tha t the amyloid is derived from an integral proteolytic fragment of lactadher in, Lactadherin is a 364-aa glycoprotein, previously known to be expressed by mammary epithelial cells as a cell surface protein and secreted as part of the milk fat globule membrane. The multidomain protein has a C-terminal domain showing homology to blood coagulation factors V and VIII, We found t hat the main constituent of aortic medial amyloid is a 50-aa-long peptide, here called medin, that is positioned within the coagulation factor-like do main of lactadherin, Our result is supported by the specific labeling of ao rtic medial amyloid in light and electron microscopy with two rabbit antise ra raised against two synthetic peptides corresponding to different parts o f medin, By using in situ hybridization we have shown that lactadherin is e xpressed by aortic medial smooth muscle cells. Furthermore, one of the synt hetic peptides forms amyloid-like fibrils in vitro. Lactadherin was not pre viously known to be an amyloid precursor protein or to be expressed in aort ic tissue. The structure of lactadherin may implicate an important regulato ry function in the aorta.