desmosine and Dilatation--Pathologic

In Marfan syndrome, mutations of the fibrillin gene (FBN1) lead to aneurysm of the thoracic aorta, making the aortic wall more susceptible to dissection, but the precise sequence of events underlying aneurysm formation is unknown. We used a rodent model of Marfan syndrome, the mgR/mgR mouse (with mgR: hypomorphic FBN1 mutation), which underexpresses FBN1, to distinguish between a defect in the early formation of elastic fibers and the later disruption of elastic fibers. The content of desmosine plus isodesmosine was used as an index of early elastogenesis; disruption of elastic fibers was analyzed by histomorphometry. Because disruption of the medial elastic fibers may produce aortic stiffening, so amplifying the aneurysmal process, we measured thoracoabdominal pulse wave velocity as an indicator of aortic wall stiffness. Both mgR/mgR and wild-type (C57BL/6J-129SV) strains were normotensive, and wall stress was not significantly modified because the increase in internal diameter (0.80+/-0.06 vs 0.63+/-0.03 mm in wild type, P<0.05) was accompanied by increased medial cross-sectional area. The aortic wall stiffened (4-fold increase in the elastic modulus-to-wall stress ratio). Desmosine content was not modified (mgR/mgR 432+/-31 vs wild type 492+/-42 microg/mg wet weight, P>0.05). Elastic fibers showed severe fragmentation: the percentage of the media occupied by elastic fibers was 18+/-3% in mgR/mgR mice vs 30+/-1% in wild-type mice, with the number of elastic segments being 1.9+/-0.2 vs 1.4+/-0.1x10(-6)/mm(2) in the wild type (both P<0.05). In conclusion, underexpression of FBN1 in mice leads to severe elastic network fragmentation but no change in cross-linking, together with aortic dilatation. This result suggests that fragmentation of the medial elastic network and not a defect in early elastogenesis is 1 of the determinants of aortic dilatation in Marfan syndrome.

Topics: Animals; Aorta; Aorta, Thoracic; Blood Pressure; Body Weight; Desmosine; Dilatation, Pathologic; Elastic Tissue; Elasticity; Female; Heart Rate; Isodesmosine; Male; Marfan Syndrome; Mice; Mice, Transgenic

The activity of lysyl oxidase, the cross-linking enzyme of elastin and collagen, was measured in culture media of human skin fibroblasts, human aortic medial smooth muscle cells (SMCs) and adventitial fibroblasts using [3H]lysine-labelled elastin substrate. In addition, biosynthesis of isodesmosine and desmosine, the cross-linking amino acids of elastin, was studied by metabolic labelling with [14C]lysine and subsequent amino acid chromatography of protein hydrolysates. Lysyl oxidase activity in culture media of skin fibroblasts and aortic smooth muscle cells increased with the growth of the cell population and was at the highest level in cultures of high cell density. Lysyl oxidase activity in the aortic cell cultures was about three times that of skin fibroblasts. Aortic smooth muscle cells synthesized at least 100 times more desmosines than skin or adventitial fibroblasts. No differences were observed in lysyl oxidase activity and synthesis of desmosines between aortic smooth muscle cells or skin fibroblasts from patients with the Marfan syndrome or other annulo-aortic ectasia (dilatation of the ascending aorta) and the corresponding controls.

Topics: Adolescent; Adult; Amino Acid Oxidoreductases; Amino Acids; Aorta; Aortic Diseases; Aortic Valve Insufficiency; Cell Line; Cells, Cultured; Child; Desmosine; Dilatation, Pathologic; Female; Fibroblasts; Humans; Male; Marfan Syndrome; Middle Aged; Protein-Lysine 6-Oxidase; Skin