PMID- 16272194
OWN - NLM
STAT- MEDLINE
DCOM- 20060502
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 290
IP  - 4
DP  - 2006 Apr
TI  - Mechanisms of low-density lipoprotein-induced expression of connective tissue 
      growth factor in human aortic endothelial cells.
PG  - H1624-34
AB  - Hyperlipidemia is a recognized risk factor for atherosclerotic vascular disease. 
      The underlying mechanisms that link lipoproteins and vascular disease are 
      undefined. Connective tissue growth factor (CTGF) is emerging as a key 
      determinant of progressive fibrotic diseases, and its expression is upregulated 
      by diabetes. To define the mechanisms through which low-density lipoproteins 
      (LDL) promote vascular injury, we evaluated whether LDL can modulate the 
      expression of CTGF and collagen IV in human aortic endothelial cells (HAECs). 
      Treatment of HAECs with LDL (50 microg/ml) for 24 h produced a significant 
      increase in the mRNA and the protein levels of CTGF and collagen IV compared with 
      unstimulated controls. To explore the mechanisms by which LDL regulates CTGF and 
      collagen IV expression in HAECs, we determined first if CTGF and collagen IV are 
      downstream targets for regulation by transforming growth factor-beta (TGF-beta). 
      The results demonstrated that TGF-beta produced a concentration-dependent 
      increase in the protein levels of CTGF. To assess whether the induction of CTGF 
      in response to LDL is mediated via autocrine activation of TGF-beta, HAECs were 
      treated with LDL for 24 h in the presence and absence of anti-TGF-beta 
      neutralizing antibodies (anti-TGF-beta NA). The results demonstrated that the 
      increase in CTGF induced by LDL was significantly inhibited by the anti-TGF-beta 
      NA. To investigate the upstream mediators of TGF-beta on activity of CTGF in 
      response to LDL, HAECs were treated with LDL for 24 h in the presence and absence 
      of cell-permeable MAPK inhibitors. Inhibition of p38(mapk) activities did not 
      affect LDL-induced TGF-beta1, CTGF, and collagen IV expression. On the other 
      hand, SP-600125, a specific inhibitor of c-Jun NH(2)-terminal kinase, suppressed 
      LDL-induced TGF-beta, CTGF, and collagen IV expression, and PD-98059, a selective 
      inhibitor of p44/42(mapk), suppressed LDL-induced TGF-beta and CTGF expression. 
      These findings are the first to implicate the MAPK pathway and TGF-beta as key 
      players in LDL signaling, leading to CTGF and collagen IV expression in HAECs. 
      The data also point to a potential mechanistic pathway through which lipoproteins 
      may promote vascular injury.
FAU - Sohn, Mimi
AU  - Sohn M
AD  - Dept. of Medicine, Div. of Endocrinology, Medical University of South Carolina, 
      Charleston, SC 29425, USA.
FAU - Tan, Yan
AU  - Tan Y
FAU - Wang, Bing
AU  - Wang B
FAU - Klein, Richard L
AU  - Klein RL
FAU - Trojanowska, Maria
AU  - Trojanowska M
FAU - Jaffa, Ayad A
AU  - Jaffa AA
LA  - eng
GR  - DK-46543/DK/NIDDK NIH HHS/United States
GR  - HL-55782/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20051104
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (CCN2 protein, human)
RN  - 0 (Collagen Type IV)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (Transforming Growth Factor beta)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
SB  - IM
MH  - Aorta/cytology/drug effects/*metabolism
MH  - Cells, Cultured
MH  - Collagen Type IV/*metabolism
MH  - Connective Tissue Growth Factor
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Humans
MH  - Immediate-Early Proteins/*metabolism
MH  - Intercellular Signaling Peptides and Proteins/*metabolism
MH  - Lipoproteins, LDL/*administration & dosage
MH  - Transforming Growth Factor beta/*administration & dosage
EDAT- 2005/11/08 09:00
MHDA- 2006/05/04 09:00
CRDT- 2005/11/08 09:00
PHST- 2005/11/08 09:00 [pubmed]
PHST- 2006/05/04 09:00 [medline]
PHST- 2005/11/08 09:00 [entrez]
AID - 01233.2004 [pii]
AID - 10.1152/ajpheart.01233.2004 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1624-34. doi: 
      10.1152/ajpheart.01233.2004. Epub 2005 Nov 4.