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-synthase gene transfer and 3-Deazaadenosine ameliorate inflammatory response in endothelial cells
1 Physiology/Biophysics, University of Louisville, Louisville, Kentucky, United States
2 Physiology/Biophysics, University of Louisville, Louisville, Kentucky, United States; Physiology and Biophysics, University of Louisville, Louisville, Kentucky, United States
3 Physiology/Biophysics, University of Louisville, Louisville, Kentucky, United States; Department of Physiology and Biophysics, University of Louisville Health Sciences Center, Louisville, Kentucky, United States
* To whom correspondence should be addressed. E-mail: suresh.tyagi{at}louisville.edu.
Although elevated levels of homocysteine (Hcy) known as Hyperhomocysteinemia (HHcy) are associated with increase inflammation and vascular remodeling, the mechanism of Hcy-mediated inflammation and vascular remodeling is unclear. The matrix metalloproteinases (MMPs) and adhesion molecules play important role in vascular remodeling. We hypothesized that HHcy induced inflammation by increasing adhesion molecules and matrix protein expression. Endothelial cells were supplemented with high methionine and Hcy accumulation was measured by HPLC. Nitric oxide (NO) bioavailability was detected by a NO-probe. The protein expression was measured by Western blot. MMP-9 activity was detected by gelatin-gel-zymography. We demonstrated that methionine supplement promoted up regulation of ICAM-1 and VCAM-1 through increased Hcy accumulation. In addition, increased synthesis of collagen type 1 was also observed. MMP-9 gene expression and protein activity were increased in methionine supplement groups. 3-deazaadenosine (DZA), an adenosine analogue, prevented high methionine-induced ICAM-1 and VCAM-1 expression and collagen type-1 synthesis. Transfection of endothelial cells with cystathionine 
-synthase (CBS) gene construct, which converted homocysteine to cystathionine, reduced Hcy accumulation in high methionine fed cells. CBS gene transfection reduced the inflammatory response, as evident by attenuated ICAM-1 and VCAM-1 expression. Furthermore, collagen type-1 expression and MMP-9 activity were dramatically attenuated with CBS gene transfection. These results suggested that methionine supplement increased Hcy accumulation which was associated with inflammatory response and matrix remodeling such as collagen type-1 synthesis and MMP-9 activity. Also, in vitro DZA and CBS gene therapy successfully treated the HHcy induced inflammatory reaction in the methionine metabolism pathway.
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