PMID- 17855772
OWN - NLM
STAT- MEDLINE
DCOM- 20080304
LR  - 20200930
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 293
IP  - 6
DP  - 2007 Dec
TI  - Cystathionine-beta-synthase gene transfer and 3-deazaadenosine ameliorate 
      inflammatory response in endothelial cells.
PG  - C1779-87
AB  - Although elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia 
      (HHcy) are associated with increased inflammation and vascular remodeling, the 
      mechanism of Hcy-mediated inflammation and vascular remodeling is unclear. The 
      matrix metalloproteinases (MMPs) and adhesion molecules play an important role in 
      vascular remodeling. We hypothesized that HHcy induces 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 analysis. MMP-9 activity was detected by 
      gelatin-gel zymography. We demonstrated that methionine supplement promoted 
      upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell 
      adhesion molecule-1 (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-beta-synthase (CBS) gene construct, which 
      converts Hcy 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. However, in vitro DZA and CBS gene therapy 
      successfully treated the HHcy-induced inflammatory reaction in the methionine 
      metabolism pathway.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology & Biophysics, University of Louisville School of 
      Medicine, Louisville, KY 40202, USA.
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Kumar, Munish
AU  - Kumar M
FAU - Moshal, Karni S
AU  - Moshal KS
FAU - Rodriguez, Walter E
AU  - Rodriguez WE
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - HL71010/HL/NHLBI NIH HHS/United States
GR  - HL88012/HL/NHLBI NIH HHS/United States
GR  - NS51568/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070913
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Collagen Type I)
RN  - 0 (Inflammation Mediators)
RN  - 037V4520IY (3-deazaadenosine)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - AE28F7PNPL (Methionine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - M351LCX45Y (Tubercidin)
SB  - IM
MH  - Animals
MH  - Cell Adhesion Molecules/metabolism
MH  - Cells, Cultured
MH  - Collagen Type I/biosynthesis
MH  - Cystathionine beta-Synthase/genetics/*metabolism
MH  - Endothelial Cells/*metabolism
MH  - Extracellular Matrix/*metabolism
MH  - Genetic Therapy
MH  - Homocysteine/metabolism
MH  - Hyperhomocysteinemia/drug therapy/*metabolism
MH  - Inflammation Mediators/*metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Methionine/administration & dosage
MH  - Mice
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type III/antagonists & inhibitors
MH  - Transfection
MH  - Tubercidin/therapeutic use
EDAT- 2007/09/15 09:00
MHDA- 2008/03/05 09:00
CRDT- 2007/09/15 09:00
PHST- 2007/09/15 09:00 [pubmed]
PHST- 2008/03/05 09:00 [medline]
PHST- 2007/09/15 09:00 [entrez]
AID - 00207.2007 [pii]
AID - 10.1152/ajpcell.00207.2007 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2007 Dec;293(6):C1779-87. doi: 
      10.1152/ajpcell.00207.2007. Epub 2007 Sep 13.