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Homocysteine and Oxidative Mechanisms of Vascular Remodeling
Author(s) -
Steed Mesia Moore,
Tyagi Neetu,
Moshal Karni,
Tyagi Suresh C.
Publication year - 2007
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.21.6.a1217-b
Subject(s) - elastin , hyperhomocysteinemia , chemistry , medicine , reactive oxygen species , homocysteine , oxidative stress , zymography , endocrinology , masson's trichrome stain , superoxide , matrix metalloproteinase , pathology , biochemistry , fibrosis , enzyme
Homocysteine (Hcy) is a risk factor for the development of hypertension, stroke, as well as for cardiovascular, renal, neuronal and liver diseases. Clinical studies have reported that the development of disease in cases of mild hyperhomocysteinemia (HHcy) was related to vascular remodeling but few data are available on the degradative mechanisms responsible for the imbalanced turnover of vascular components. We, therefore, designed the present study to explore the hypothesis that mild HHcy increases reactive oxygen species (ROS) and subsequent matrix metalloproteinase (MMP) activity in the vasculature due to changes in nitric oxide (NO) bioavailability. Experiments were performed in a mouse model of mild HHcy induced by oral administration of Hcy (.67g/L) for 6–8 weeks. Plasma levels of Hcy were measured by ELISA assay. All subsequent experiments were performed on isolated descending thoracic aorta. Hematoxylin and eosin was used to assess general tissue morphology, Trichrome for collagen and Van Geison’s stain for elastin. An in situ assay using oxidative fluorescent dye, dihydroethidium, measured superoxide generation. MMP −2 and −9 expression and activity were measured by Western Blot and 2% gelatin zymography, respectively. An increase in superoxide in the vessel wall is partially responsible for the changes in NO bioavailability accompanied by differential eNOS and iNOS expression. An elevation in MMP −2 activity and the appearance of MMP −9 (indicator of remodeling) was seen in the aorta of WT +Hcy animals. The aortic wall of WT + Hcy exhibited gross disorganization and thickening of the extracellular matrix along with extensive collagen deposition. These results suggest that vessel wall remodeling in mild HHcy is likely due to increase oxidative stress and MMP activity due to changes in NO bioavailability.