PMID- 17990952
OWN - NLM
STAT- MEDLINE
DCOM- 20080401
LR  - 20161018
IS  - 1434-6621 (Print)
IS  - 1434-6621 (Linking)
VI  - 45
IP  - 12
DP  - 2007
TI  - Synergism between AT1 receptor and hyperhomocysteinemia during vascular 
      remodeling.
PG  - 1771-6
AB  - BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor of 
      cardiovascular diseases. Extracellular signal-regulated kinase-1/2 (ERK-1/2) and 
      the JAK/STAT pathway kinase, signal transducer and activator of transcription 3 
      (STAT3), are involved in matrix metalloproteinase-9 (MMP-9) induction and matrix 
      remodeling. However, their role in homocysteine (Hcy)-mediated MMP-9 induction 
      and matrix remodeling is unclear. Clinical and experimental evidence indicates 
      that HHcy and activation of the renin-angiotensin system, mediated by angiotensin 
      II type 1 (AT1) receptor, are involved in a variety of vascular pathologies. 
      Despite this fact, the relationship between HHcy and activation of the 
      renin-angiotensin system has not been comprehensively characterized. Therefore, 
      we hypothesized that Hcy activates AT1 receptor that potentiates STAT3 via 
      ERK-1/2 phosphorylation. STAT3 modulates target MMP-9 and collagen, resulting in 
      vascular remodeling. METHODS: Mouse aortic endothelial cells (MAEC) were treated 
      with various doses of Hcy for different time periods. The levels of AT1 receptor, 
      ERK-1/2, STAT3, MMP-9 and collagen type-1 were measured by immunoblot analyses. 
      The activation of ERK-1/2 and STAT3 were determined by measuring ERK-1/2 
      phosphorylation and phosphoserine (727) STAT3. RESULTS: Although Hcy 
      dose-dependently induced AT1 receptor expression in the endothelial cells, a 
      significant induction was observed at 100 microM at 48 h. We investigated 
      Hcy-induced ERK-1/2 and STAT3 phosphorylation through AT1 receptor induction, and 
      our results suggest that Hcy activated AT1 receptor which led to ERK-1/2 and 
      STAT3 phosphorylation. In addition, findings of this study suggest that 
      Hcy-mediated STAT3 activation regulated MMP-9 and collagen type-1. However, AT1 
      receptor blocker, valsartan, and the specific STAT3 inhibitor peptide attenuated 
      MMP-9 and collagen type-1 induction. CONCLUSIONS: These findings demonstrate for 
      the first time the contribution of AT1 receptor in HHcy-induced atherosclerotic 
      diseases; Hcy-induced activation of AT1 receptor involves MMP-9 and collagen 
      type-1 modulation using ERK-1/2 and STAT3 signaling cascades.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, KY 40202, USA.
FAU - Herrmann, Markus
AU  - Herrmann M
FAU - Herrmann, Wolfgang
AU  - Herrmann W
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - HL71010/HL/NHLBI NIH HHS/United States
GR  - HL74185/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
PL  - Germany
TA  - Clin Chem Lab Med
JT  - Clinical chemistry and laboratory medicine
JID - 9806306
RN  - 0 (Collagen Type I)
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - Blood Vessels/*physiopathology
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Collagen Type I/metabolism
MH  - Endothelium, Vascular/enzymology/*physiopathology
MH  - Homocysteine/physiology
MH  - Hyperhomocysteinemia/*physiopathology
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Receptor, Angiotensin, Type 1/*physiology
MH  - STAT3 Transcription Factor/metabolism
EDAT- 2007/11/10 09:00
MHDA- 2008/04/02 09:00
CRDT- 2007/11/10 09:00
PHST- 2007/11/10 09:00 [pubmed]
PHST- 2008/04/02 09:00 [medline]
PHST- 2007/11/10 09:00 [entrez]
AID - 10.1515/CCLM.2007.354 [doi]
PST - ppublish
SO  - Clin Chem Lab Med. 2007;45(12):1771-6. doi: 10.1515/CCLM.2007.354.