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Functional consequences of the collagen/elastin switch in vascular remodeling in Hyperhomocysteinemia
Author(s) -
Steed Mesia Moore,
Rodriquez Walter,
Tyagi Neetu,
Tyagi Suresh C.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1147.8
Subject(s) - elastin , enos , chemistry , hyperhomocysteinemia , oxidative stress , matrix metalloproteinase , medicine , endocrinology , extracellular matrix , homocysteine , nitric oxide , biochemistry , pathology , biology , nitric oxide synthase
Homocysteine (Hcy), the cholesterol of the 21 st century, has emerged as a novel independent risk factor for the development of cardiovascular disease. Elevated circulating Hcy or hyperhomocysteinemia (HHcy) mediates the atherogenic collagen/elastin switch in vascular tissue and resulting reduction in vascular compliance. We hypothesize that the differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of matrix metalloprotineases (MMPs) resulting in vascular remodeling in response to HHcy. The overall goal is to elucidate the contribution of the nitric oxide synthases (NOS isoforms); endothelial, neural and inducible in the collagen/elastin switch. Experiments were performed on six groups of animals (WT, eNOS−/−, iNOS−/− with and without Hcy treatment [.67g/L] for 8–12weeks). In vivo echograph was performed to assess aortic timed flow velocity for indirect compliance measurement. Histological determination of collagen and elastin with Trichrome and Van Geison's stains, respectively was performed. In situ measurement of superoxide generation using dihydroethidium was used. Differential expression of eNOS, iNOS, nitrotyrosine, MMP ‐2 and ‐9 and elastin were measured by quantitative PCR and Western blot analysis. The 2% gelatin zymography was used to assess MMP activity. The increase in superoxided and robust activity of MMP‐9in eNOS−/−, WT+HCY and eNOS−/−+Hcy was accompanied by the gross disorganization and thickening of the extracellular matrix along with extensive collagen deposition and elastin degradation (collagen/elastin switch) resulting in a decrease in aortic timed flow velocity. Results show that increased activity of iNOS is a key contributor to HHcy mediated collagen/elastin switch and resulting decline in aortic compliance.