(Circulation. 2000;102:1970.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells
The Potential Role of Transcription Factor NF-
B
From the Departments of Medicine and Physiology, University of Arkansas and VA Medical Center, Little Rock (D.L., J.L.M.); the University of Rome, Tor Vergata, Rome, Italy (F.R.); and the Department of Forensic Medicine, University of Uppsala, Uppsala, Sweden (T.S.).
Correspondence to J.L. Mehta, MD, PhD, University of Arkansas Medical Science, Mail Slot 532, 4301 West Markham, Little Rock, AR 72205-7199.
Background—We demonstrated
earlier that angiotensin II (Ang II), by AT1
receptor activation, upregulates oxidized LDL (ox-LDL)
endothelial receptor LOX-1 gene expression and uptake
of ox-LDL in human coronary artery endothelial
cells (HCAECs). In this study, we investigated the regulation of Ang II
receptors (AT1R and AT2R) by ox-LDL and the role of the redox-sensitive
transcription factor NF-
B in this process.
Methods and Results—HCAECs were incubated with ox-LDL for 24
hours. Ox-LDL (10 to 40 µg protein/mL) upregulated AT1R but not AT2R,
mRNA, or protein. Ox-LDL degraded IB
in cytoplasm and
activated transcription factor NF-B (P65) in HCAEC nuclear
extract. Treatment of cells with the antioxidant
-tocopherol (10 to 50 µmol/L) attenuated
ox-LDL–mediated degradation of IB and activation of NF-B
(P65) and inhibited the upregulation of AT1R mRNA and protein. The role
of NF-B signal transduction was further examined by use of an
NF-B inhibitor, caffeic acid phenethyl ester (CAPE).
Pretreatment of cells with CAPE inhibited ox-LDL–mediated degradation
of IB and NF-B activation and inhibited ox-LDL–induced
upregulation of AT1R expression. Incubation of cells with both ox-LDL
and Ang II increased cell injury, measured as cell viability and LDH
release, compared with either ox-LDL or Ang II alone.
-Tocopherol as well as the specific AT1R blocker CV11974
(candesartan) attenuated the cell-injurious effects of ox-LDL.
Conclusions—These observations suggest an important role of
ox-LDL–mediated AT1R upregulation in cell injury. In this process,
NF-B activation seems to play a critical role in signal
transduction. These findings provide a basis for the use of
antioxidants and AT1R blockers in designing therapy of
atherosclerosis.
Key Words: angiotensin • receptors • lipoproteins • endothelium • antioxidants
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