(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.
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Abstract |
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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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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II (Ang II) activates at least 2 distinct types of cell-surface receptors, the type 1 (AT1R) and the type 2 (AT2R).1 2 Most studies suggest that AT1R activation mediates most known effects of Ang II in the cardiac tissues.2 3 However, some studies also show that activation of the AT2R receptor mediates myocardial ischemia-reperfusion injury4 and exerts proapoptotic effect on myocytes.5 Both AT1R and AT2R exist in rat coronary artery endothelial cells.6 Recent work from our laboratory7 indicates that both AT1R and AT2R exist in human coronary artery endothelial cells (HCAECs), and AT1R activation induces apoptosis of HCAECs. Another recent study8 showed that activation of AT1R causes myocardial dysfunction during myocardial ischemia-reperfusion in isolated rat hearts.
In atherosclerosis, oxidized LDL (ox-LDL) accumulates
in the vessel walls,9 decreases generation of nitric oxide
(NO),10 and causes endothelial
dysfunction.11 Ox-LDL is cytotoxic12 and acts
as a chemotactic factor for monocytes,13 leading to the
accumulation of inflammatory cells and the generation of oxygen-derived
free radicals that can inactivate
endothelium-derived NO.14 Ox-LDL induces
apoptosis in vascular smooth muscle cells,15
monocytes/macrophages,16 and
endothelial cells.17 On the basis of these
considerations, oxidative modification of LDL is considered a key
trigger in the initiation and progression of
atherosclerosis.18 A recent study by
Maziere et al19 demonstrated that ox-LDL induces
activation of transcription factor NF-B in
endothelial cells and causes cell injury.
Activated NF-B has indeed been detected in
endothelial cells of atherosclerotic
plaques.20
There is increasing evidence for an interaction between
hyperlipidemia and the renin-angiotensin
system in atherogenesis.21 22 23 For example, AT1R
expression is upregulated by LDL in vascular smooth muscle
cells.21 Ang II facilitates oxidation of
LDL22 and its uptake by scavenger receptors on
monocytes/macrophages.23 We have recently
demonstrated upregulation of specific lectin-like receptors for ox-LDL
(LOX-1) in response to Ang II.24 In the present study,
we provide evidence that ox-LDL upregulates expression of Ang II type
AT1R in cultured HCAECs. We also demonstrate a critical role of
transcription factor NF-B activation in this process.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cell Culture
The methodology for culture of HCAECs has been described previously.17 24 In brief, the initial batch of HCAECs was purchased from Clonetics Corp. The endothelial cells were pure on the basis of morphology and staining for factor VIII and acetylated LDL. HCAECs were cultured in microvascular endothelium growth medium (Clonetics) that consisted of 500 mL endothelial cell basal medium, 5 ng human recombinant epidermal growth factor, 0.5 mg hydrocortisone, 25 mg gentamycin, 50 µg amphotericin B, 6 mg bovine brain extract, and 25 mL FBS. Fourth-generation HCAECs were used in this study.
HCAECs were incubated with ox-LDL (10 and 40 µg protein/mL) for 24
hours, and expression of AT1R and AT2R was determined. Parallel groups
of HCAECs were incubated with ox-LDL (40 µg protein/mL) alone or with
the antioxidant -tocopherol (10 and 50 µmol/L) to
study degradation of IB, NF-B activation, and AT1R expression.
Parallel groups of HCAECs also were pretreated with the antioxidant
-tocopherol, the AT1R blocker CV11974 (candesartan,
10-6 mol/L), or the AT2R
blocker PD123319 (10-6
mol/L) for 30 minutes, and HCAECs then were exposed to ox-LDL, Ang II,
or both to study degradation of IB, activation of NF-B, and
induction of cell injury (cell viability and LDH release). To further
determine the role of NF-B activation, cells were incubated with
TNF- (40 ng/mL) and the NF-B inhibitor caffeic acid
phenethyl ester (CAPE), 20 µg/mL, and degradation of IB and
NF-B activation and AT1R expression was studied. TNF- served as a
positive control for NF-B activation by ox-LDL. The concentrations
of these reagents were based on previous
studies.17 25 26
Preparation of Lipoproteins
Native LDL and ox-LDL were prepared as described
earlier.17 LDL was oxidized by exposure to
CuSO4 (5 µmol/L free
Cu2+) in PBS at 37°C for 24 hours. The
thiobarbituric acid–reactive substances content of ox-LDL was
17.5±1.6 versus 0.38±0.11 nmol/100 µg protein in the native-LDL
preparation (P<0.01). LDL and ox-LDL were kept in 50
mmol/L Tris-HCl, 0.15 mol/L NaCl, and 2 mmol/L EDTA at pH 7.4 and
were used within 10 days of preparation. Endotoxin concentration in the
LDL was checked with the E-Toxate kit (Sigma) and found to be
consistently <0.005 endotoxin units/mL (lowest detection
limit).
RT-PCR for AT1R and AT2R
The detailed methodology for reverse transcription–polymerase
chain reaction (RT-PCR) identification of AT1R and AT2R in HCAECs was
published recently.24 Essentially, the reverse-transcribed
material was amplified with Taq DNA polymerase (Promega)
with a primer pair specific to human AT1R receptor (forward primer,
5'-TCATTTACTTTTATATTGTAA-3'; reverse primer,
5'-TGAATTTCATAAGCCTTCTT-3'). PCR product was 532 bp. For PCR, 35
cycles were used at 94°C for 1 minute, 50°C for 1 minute, and
72°C for 2 minutes. The primer pair specific to human AT2R receptor
was (forward primer) 5'-AATATGAAG-GGCAACTCCAC-3' and
(reverse primer) 5'-TTAAGAC-ACAAAGGTCTCCAT-3'. The PCR
product was 1100 bp. For PCR, 35 cycles were used at 94°C for 1
minute, 58°C for 1 minute, and 72°C for 2 minute.
Immunoprecipitation and Western Blot for AT1R and AT2R
Cell lysates (120 µg) were subjected to immunoprecipitation
and then Western analysis. In brief, the cell lysates
containing equal amounts of soluble proteins were immunoprecipitated.
Precipitates were washed and then resuspended in SDS-PAGE sample buffer
and boiled for 5 minutes. Samples were separated by 12% SDS-PAGE, and
then transferred to nitrocellulose membranes. After incubation in
blocking solution (4% nonfat milk, Sigma), membranes were incubated
with primary antibody (polyclonal antibody to AT1R or polyclonal
antibody to AT2R, Santa Cruz Laboratory) for 2 hours at room
temperature. Membranes were washed and then incubated with 1:3000
dilution secondary antibody (Amersham) for 1 hour, detected with the
ECL system, and relative intensities of protein bands were
analyzed by MSF-300G Scanner (Microtek
Laboratory).27
Preparation of Nuclear Extracts and Western Blot for
NF-B
The detailed methodology for preparation of nuclear extracts and
Western blot for NF-B in HCAECs has been published
recently.28 We used a monoclonal antibody to the P65
subunit of NF-B from mouse to mouse hybrid cells (Boehringer
Mannheim). The antibody recognizes an epitope overlapping the nuclear
location signal of the P65 subunit and therefore selectively binds the
activated form of NF-B.
Western Blot for IB
The detailed methodology for Western blot for IB in HCAECs
was published recently.28 The antibody used was a rabbit
polyclonal anti-IB (Santa Cruz Biotechnology).
Measurement of LDH
HCAEC supernatants were collected for determination of LDH. An
enzyme activity method based on oxidation of lactate with measurement
of rate of increase in absorbance at 340 nm was used. The activity of
LDH was expressed as units per milligram protein.24
Cell Viability
A small aliquot of cells was incubated in 0.1% trypan blue for
a few minutes, and the cells were viewed under a light microscope. Dead
cells are permeable to trypan blue and thus become colored, whereas
viable cells do not take up the dye. By counting 100 cells, the
percentage of viable cells was calculated.24
Data Analysis
All data represent the mean of duplicate samples from 6
independently performed experiments. Data are presented as
mean±SD. Statistical significance was determined in multiple
comparisons among independent groups of data in which ANOVA and the F
test indicated the presence of significant differences. A value of
P<0.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ox-LDL and Regulation of AT1R and AT2R in HCAECs
As described earlier,24 AT1R and AT2R mRNA and protein were identified by RT-PCR and Western blot analyses, respectively, in all HCAEC aliquots. Incubation of HCAECs with ox-LDL (10 and 40 µg protein/mL) induced progressive upregulation of AT1R mRNA. Incubation of cells with ox-LDL had no significant effect on AT2R mRNA (Figure 1
). Incubation with 80
µg/mL of ox-LDL had a smaller effect on AT1R expression than the 40
µg/mL concentration (data not shown), perhaps a result of the
cell-injurious effect of high concentrations of ox-LDL.
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Incubation of HCAECs with ox-LDL (10 and 40 µg protein/mL) induced a
progressive increase in AT1R protein expression (P<0.01).
Incubation of cells with ox-LDL had no significant effect on AT2R
protein expression. Results of a representative
experiment and summary of data from multiple experiments are shown in
Figure 2.
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Ox-LDL and Degradation of IB and Activation of NF-B and the
Effect of -Tocopherol
Treatment of HCAECs with ox-LDL (40 µg protein/mL) degraded
IB and activated NF-B(P65) compared with control
(P<0.01). Pretreatment of HCAECs with
-tocopherol (10 and 50 µmol/L) before exposure of
cells to ox-LDL consistently inhibited ox-LDL–mediated
degradation of IB and activation of NF-B compared with ox-LDL
alone. The effect of 50 µmol/L concentration was greater than
that of 10 µmol/L of -tocopherol on both IB
and NF-B (P65) (Figure 3).
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Modulatory Effect of -Tocopherol on AT1R Expression
by Ox-LDL
The presence of -tocopherol in the culture
medium before the cells were exposed to ox-LDL decreased
ox-LDL–mediated upregulation of AT1R mRNA (P<0.05 versus
ox-LDL alone). The higher concentration of -tocopherol
(50 µmol/L) was more effective than the lower concentration of
-tocopherol (10 µmol/L) in this effect
(P<0.01) (Figure 4).
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The pretreatment of HCAECs with -tocopherol before the
cells were exposed to ox-LDL also decreased ox-LDL–mediated
upregulation of AT1R protein (P<0.01 versus ox-LDL alone).
The higher concentration of -tocopherol (50
µmol/L) was more effective than the lower concentration of
-tocopherol (10 µmol/L) in this effect
(P<0.01) (Figure 5).
-Tocopherol alone did not affect AT1R mRNA (Figure 4
) and protein expression (Figure 5).
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Effect of NF-B Inhibitor CAPE on ox-LDL– or
TNF-–Mediated NF-B Activation
To confirm the role of NF-B in ox-LDL–induced AT1R expression,
we used CAPE as a potent inhibitor of
NF-B.26 TNF- was used as a positive control for
NF-B activation. We found that ox-LDL and TNF- both significantly
degraded IB in cytoplasm and activated NF-B in the
nuclear extract. CAPE markedly prevented ox-LDL– or TNF-–mediated
effects. CAPE alone did not affect IB degradation and NF-B
activation (Figure 6).
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Effect of NF-B Inhibitor CAPE on AT1R
Expression
Ox-LDL upregulated AT1R mRNA and protein as described earlier.
TNF- also significantly induced degradation of IB, induced
NF-B activation, and upregulated AT1R mRNA and protein expression.
Pretreatment of cells with CAPE markedly attenuated ox-LDL– and
TNF-–induced upregulation of AT1R mRNA and protein expression. CAPE
alone did not affect AT1R mRNA and protein expression (Figure 7).
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Cell Injury in Response to Ox-LDL and Ang II
Treatment of HCAECs with either ox-LDL or Ang II alone caused a
modest increase in LDH release and decrease in cell viability. The
presence of both ox-LDL and Ang II further increased cell injury, as
measured by cell viability and LDH release, compared with ox-LDL or Ang
II alone (P<0.05). Notably, -tocopherol
decreased ox-LDL–induced cell injury. The AT1R blocker CV11974, but
not the AT2R blocker PD123319, inhibited ox-LDL–induced cell injury.
In control experiments, -tocopherol (50 µmol/L)
decreased cell injury in response to ox-LDL and CV11974 decreased cell
injury in response to Ang II. These data are summarized in Figures 8 and 9.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ox-LDL induces apoptosis and necrosis and upregulates its own receptors, LOX-1, in HCAECs.28 29 The present study indicates that ox-LDL also upregulates the expression of AT1R, but not AT2R, in cultured HCAECs. This study also shows that the degradation of I
B and activation of NFB (P65) play an
important role in the signal transduction pathway in this action of
ox-LDL. The critical role of IB and NF-B became evident in
experiments in which -tocopherol and CAPE inhibited the
upregulation of AT1R expression by ox-LDL. The importance of
upregulation of AT1R expression in HCAECs became evident from the
effects of CV11974, a specific AT1R blocker that markedly decreased the
injurious effect of ox-LDL and Ang II.
Ox-LDL and Regulation of Ang II Receptors
Nickenig et al27 showed that
hyperlipidemia increases the expression of AT1R
receptor in rat cultured vascular smooth muscle cells by 2- to
3-fold. They also showed upregulation of AT1R gene expression when rat
vascular smooth muscle cells were exposed to LDL. A recent study from
our laboratory demonstrated marked upregulation of AT1R in the
atherosclerotic rabbit arteries.30 The importance of AT1R
expression in hypercholesterolemic rabbits became
evident from increased vasoconstrictor response to Ang II and
diminished response to the endothelium-dependent
vasodilator acetylcholine.30 Ang II has also been shown to
facilitate oxidization of LDL in macrophages.22
These observations suggest an interaction between ox-LDL and Ang II. In
the present study, we show that ox-LDL upregulates AT1R mRNA and
protein expression, whereas the expression of AT2R remains largely
unaffected in cultured HCAECs. We did not further examine the
transcriptional and posttranscriptional mechanisms of ox-LDL–induced
AT1R expression in this study. We emphasized the effects of ox-LDL on
AT1R expression and subsequent functional significance of AT1R
expression. We recently provided evidence that Ang II upregulates
specific LOX-1 on HCAECs and facilitates the uptake of
I125-labeled ox-LDL into these cells; this effect
of Ang II can be blocked with specific blockade of AT1R.24
Collectively, these studies provide strong evidence of cross talk
between ox-LDL and Ang II in the regulation of cell dysfunction and
injury.
Ox-LDL and the Transcription Factor NF-B
NF-B is an oncogenic protein that regulates transcription of a
variety of cellular genes, including immune and inflammatory response
and growth control.31 NF-B is present in the
cytosol as a heterodimer composed of NF-B1
(P50) and Rel (P65) subunits bound to an inhibitor protein,
IB. Degradation of IB protein seems to be necessary for the
activation of NF-B.32 After activation, NF-B
translocates from the cytosol to the nucleus of the cell, binds to
specific DNA sequences, and initiates transcription. Maziere et
al19 showed that ox-LDL activates NF-B in
fibroblasts, smooth muscle cells, and endothelial
cells. Collins33 suggested oxidative activation of
endothelial cell transcription factors, especially
NF-B, as a mechanism for changing endothelial cell
phenotype and for initiating atherosclerotic lesions. Hernan
dez-Presa and colleagues20 provided direct evidence for
NF-B activation in early atherosclerotic lesions. Other studies have
shown a critical role of NF-B activation in apoptosis in
myocytes34 and endothelial
cells.35 In the present study, we demonstrate that
ox-LDL degrades IB protein and activates NF-B in
HCAECs. An obvious question relates to the basis of degradation of
IB and activation of NF-B by ox-LDL. ox-LDL–induced free
radical release may play a critical role in this process. The
redox-sensitive nature of NF-B activation became clear from the
observation that a free radical scavenger, -tocopherol,
and the NF-B inhibitor CAPE not only inhibited
ox-LDL–mediated degradation of IB and activation of NF-B but
also inhibited the upregulation of AT1R in HCAECs. A recent
study26 reported that CAPE inhibits transcription factor
NF-B activation without any effect on other transcription factors,
such as AP-1, Oct-1, and TFIID. This study26 also showed
that CAPE exerts its effects by inhibiting reactive oxygen
intermediates. These observations collectively indicate that activation
of NF-B may be an important signal transduction pathway in the
effects of ox-LDL on HCAECs.
Interaction Between ox-LDL and Ang II in Cell Injury
Experimental studies21 24 27 30 suggest that cross
talk between hypercholesterolemia and Ang II
may have pathophysiological significance. For
example, upregulation of AT1R mediated by
hypercholesterolemia leads to enhanced Ang
II–induced vasoconstriction.27 30 In contrast, Ang II
increases oxidation of LDL22 and upregulates ox-LDL
endothelial receptor (LOX-1).24
Both Ang II and ox-LDL are important factors in inducing
endothelial dysfunction and injury. Work from our
laboratory has shown that Ang II7 and
ox-LDL17 decrease NO generation and increase lipid
peroxidation and LDH release in cultured HCAECs. Both Ang II and ox-LDL
enhance anoxia-reoxygenation–mediated HCAEC injury.
Work from other laboratories36 37 also suggests that
ox-LDL and Ang II cause injury to endothelial cells. In
the present study, we demonstrate that ox-LDL and Ang II induce
cell injury in a cumulative fashion. The mechanism of ox-LDL–mediated
cell injury may be related, at least in part, to the upregulation of
AT1R expression. NF-B activation may play an important role in this
process. This became evident in experiments in which
-tocopherol significantly inhibited the actions of
ox-LDL in conjunction with inhibition of upregulation of AT1R by
ox-LDL. The AT1R blocker CV11974 (candesartan) also attenuated the
cell-injurious effects of ox-LDL. These observations suggest that
-tocopherol and AT1R blockers may reduce the adverse
effect of cross talk between ox-LDL and Ang II.
In summary, this study shows that ox-LDL upregulates the expression of
AT1R, but not AT2R, in cultured human coronary
endothelial cells. The cross talk between ox-LDL and
Ang II serves to promote injury to coronary
endothelial cells. Degradation of IB and
activation of NF-B appear to be important signal transduction
pathways involved in the action of ox-LDL.
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Acknowledgments |
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This study was supported by a Merit Review Award from the VA Central Office, a contract with the Department of Defense, and funds from the Swedish Medical Research Council.
Received March 30, 2000; revision received May 22, 2000; accepted May 22, 2000.
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  M. Backlund, K. Paukku, L. Daviet, R. A. De Boer, E. Valo, S. Hautaniemi, N. Kalkkinen, A. Ehsan, K. K. Kontula, and J. Y. A. Lehtonen Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde 3-phosphate dehydrogenase Nucleic Acids Res., April 1, 2009; 37(7): 2346 - 2358. [Abstract] [Full Text] [PDF]
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 S. Van Linthout, F. Spillmann, M. Lorenz, M. Meloni, F. Jacobs, M. Egorova, V. Stangl, B. De Geest, H.-P. Schultheiss, and C. Tschope Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor Hypertension, April 1, 2009; 53(4): 682 - 687. [Abstract] [Full Text] [PDF]
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 K. K. Koh, P. C. Oh, and M. J. Quon Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res, March 1, 2009; 81(4): 649 - 659. [Abstract] [Full Text] [PDF]
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C. Hu, A. Dandapat, L. Sun, M. R. Marwali, N. Inoue, F. Sugawara, K. Inoue, Y. Kawase, K.-i. Jishage, H. Suzuki, et al. Modulation of Angiotensin II-Mediated Hypertension and Cardiac Remodeling by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Deletion Hypertension, September 1, 2008; 52(3): 556 - 562. [Abstract] [Full Text] [PDF]
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E. D. Frohlich Excitement of Clinical Investigation: New Basic Mechanisms of Action After Drug Introduction Hypertension, September 1, 2008; 52(3): 465 - 466. [Full Text] [PDF]
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 V. Mollace, S. Ragusa, I. Sacco, C. Muscoli, F. Sculco, V. Visalli, E. Palma, S. Muscoli, L. Mondello, P. Dugo, et al. The Protective Effect of Bergamot Oil Extract on Lecitine-like OxyLDL Receptor-1 Expression in Balloon Injury-related Neointima Formation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2008; 13(2): 120 - 129. [Abstract] [PDF]
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 A. Dandapat, C. Hu, L. Sun, and J. L. Mehta Small Concentrations of oxLDL Induce Capillary Tube Formation From Endothelial Cells via LOX-1 Dependent Redox-Sensitive Pathway Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2435 - 2442. [Abstract] [Full Text] [PDF]
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C. Hu, A. Dandapat, and J. L Mehta Angiotensin II Induces Capillary Formation From Endothelial Cells Via the LOX-1 Dependent Redox-Sensitive Pathway Hypertension, November 1, 2007; 50(5): 952 - 957. [Abstract] [Full Text] [PDF]
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T. S. Elton and M. M. Martin Angiotensin II Type 1 Receptor Gene Regulation: Transcriptional and Posttranscriptional Mechanisms Hypertension, May 1, 2007; 49(5): 953 - 961. [Full Text] [PDF]
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 B. Molavi, J. Chen, and J. L. Mehta Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H687 - H693. [Abstract] [Full Text] [PDF]
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 H. Morawietz, S. Erbs, J. Holtz, A. Schubert, M. Krekler, W. Goettsch, O. Kuss, V. Adams, K. Lenk, F. W. Mohr, et al. Endothelial Protection, AT1 Blockade and Cholesterol-Dependent Oxidative Stress: The EPAS Trial Circulation, July 4, 2006; 114(1_suppl): I-296 - I-301. [Abstract] [Full Text] [PDF]
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J. Chen, Y. Liu, H. Liu, P. L. Hermonat, and J. L. Mehta Molecular Dissection of Angiotensin II-Activated Human LOX-1 Promoter Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1163 - 1168. [Abstract] [Full Text] [PDF]
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J. L. Mehta, J. Chen, P. L. Hermonat, F. Romeo, and G. Novelli Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): A critical player in the development of atherosclerosis and related disorders Cardiovasc Res, January 1, 2006; 69(1): 36 - 45. [Abstract] [Full Text] [PDF]
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K. Hishikawa, T. Nakaki, and T. Fujita Oral Flavonoid Supplementation Attenuates Atherosclerosis Development in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 442 - 446. [Abstract] [Full Text] [PDF]
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K. Chen, J. Chen, D. Li, X. Zhang, and J. L. Mehta Angiotensin II Regulation of Collagen Type I Expression in Cardiac Fibroblasts: Modulation by PPAR-{gamma} Ligand Pioglitazone Hypertension, November 1, 2004; 44(5): 655 - 661. [Abstract] [Full Text] [PDF]
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 C. Muscoli, I. Sacco, W. Alecce, E. Palma, R. Nistico, N. Costa, F. Clementi, D. Rotiroti, F. Romeo, D. Salvemini, et al. The Protective Effect of Superoxide Dismutase Mimetic M40401 on Balloon Injury-Related Neointima Formation: Role of the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 44 - 50. [Abstract] [Full Text] [PDF]
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 A. R. Chade, M. D. Bentley, X. Zhu, M. Rodriguez-Porcel, S. Niemeyer, B. Amores-Arriaga, C. Napoli, E. L. Ritman, A. Lerman, and L. O. Lerman Antioxidant Intervention Prevents Renal Neovascularization in Hypercholesterolemic Pigs J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1816 - 1825. [Abstract] [Full Text] [PDF]
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S.-W. Ryoo, D.-U. Kim, M. Won, K.-S. Chung, Y.-J. Jang, G.-T. Oh, S.-K. Park, P.-J. Maeng, H.-S. Yoo, and K.-L. Hoe Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells Cardiovasc Res, April 1, 2004; 62(1): 185 - 193. [Abstract] [Full Text] [PDF]
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 T. Thum and J. Borlak Mechanistic Role of Cytochrome P450 Monooxygenases in Oxidized Low-Density Lipoprotein-Induced Vascular Injury: Therapy Through LOX-1 Receptor Antagonism? Circ. Res., January 9, 2004; 94 (1): e1 - e13. [Abstract] [Full Text] [PDF]
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J. L. Mehta, B. Hu, J. Chen, and D. Li Pioglitazone Inhibits LOX-1 Expression in Human Coronary Artery Endothelial Cells by Reducing Intracellular Superoxide Radical Generation Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2203 - 2208. [Abstract] [Full Text] [PDF]
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 B. M. Singh and J. L. Mehta Interactions Between the Renin-Angiotensin System and Dyslipidemia: Relevance in the Therapy of Hypertension and Coronary Heart Disease Arch Intern Med, June 9, 2003; 163(11): 1296 - 1304. [Abstract] [Full Text] [PDF]
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D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF]
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D. Li, L. Liu, H. Chen, T. Sawamura, and J. L. Mehta LOX-1, an Oxidized LDL Endothelial Receptor, Induces CD40/CD40L Signaling in Human Coronary Artery Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 816 - 821. [Abstract] [Full Text] [PDF]
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F. S. Gragasin, Y. Xu, I. A. Arenas, N. Kainth, and S. T. Davidge Estrogen Reduces Angiotensin II-Induced Nitric Oxide Synthase and NAD(P)H Oxidase Expression in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 38 - 44. [Abstract] [Full Text] [PDF]
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D. Li, R. M. Singh, L. Liu, H. Chen, B. M. Singh, N. Kazzaz, and J. L. Mehta Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells Cardiovasc Res, January 1, 2003; 57(1): 238 - 243. [Abstract] [Full Text] [PDF]
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 J. L. Mehta and D. Li Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1429 - 1435. [Abstract] [Full Text] [PDF]
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 S. Keidar, R. Heinrich, M. Kaplan, and M. Aviram Oxidative stress increases the expression of the angiotensin-II receptor type 1 in mouse peritoneal macrophages Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 24 - 30. [Abstract] [PDF]
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M. Yeh, N. Leitinger, R. de Martin, N. Onai, K. Matsushima, D. K. Vora, J. A. Berliner, and S. T. Reddy Increased Transcription of IL-8 in Endothelial Cells Is Differentially Regulated by TNF-{alpha} and Oxidized Phospholipids Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1585 - 1591. [Abstract] [Full Text] [PDF]
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H. Chen, D. Li, T. Saldeen, and J. L. Mehta Transforming Growth Factor-{beta}1 Modulates Oxidatively Modified LDL-Induced Expression of Adhesion Molecules: Role of LOX-1 Circ. Res., December 7, 2001; 89(12): 1155 - 1160. [Abstract] [Full Text] [PDF]
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