title: Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis.
abstract: Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.
authors.affiliation: Center for Cardiovascular Research/Institute of Pharmacology and Toxicology, Campus Charité Mitte, Charité-University Medicine Berlin, 10115 Berlin, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Kaschina
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Manuela
authors.initials: M
authors.lastname: Sommerfeld
authors.forename: U Muscha
authors.initials: UM
authors.lastname: Steckelings
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
mesh_terms: D000005:Abdomen / Q000098:blood supply; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004790:Enzyme Induction; D007704:Kininogens / Q000172:deficiency* / Q000235:genetics*; D050356:Lipid Metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D016207:Cytokines; D007704:Kininogens; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4