(Hypertension. 1999;34:976-982.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells
From the Experimental Hypertension Laboratory, MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal and Université de Montréal, Montreal, Quebec, Canada H2W 1R7.
Correspondence to Rhian M. Touyz, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail touyz{at}ircm.umontreal.ca
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Intracellular signaling events that mediate the long-term effects of Ang II in vascular smooth muscle cells are unclear, but oxidative stress may play an important role. This study examined the ability of Ang II to generate reactive oxygen species and investigated the putative role of phospholipase D (PLD)–dependent signaling pathways for its production in human vascular smooth muscle cells. In addition, we assessed whether redox-sensitive pathways influence Ang II–stimulated cell growth. Primary and low-passage cells (passages 1 to 4) derived from resistance arteries of subcutaneous gluteal biopsies from healthy subjects were studied. Oxidative stress was measured with the fluorescent probe 5-(and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) (8 µmol/L), and the role of PLD was assessed with the PLD inhibitor D-erythro-sphingosine, dihydro (sphinganine) (10 µmol/L). To determine whether NADH/NADPH oxidase contributes to production of reactive oxygen species, Ang II–stimulated cells were pretreated with the specific flavoprotein inhibitor diphenylene iodinium (DPI) (10 µmol/L). DNA and protein synthesis were determined by [3H]thymidine and [3H]leucine incorporation, respectively. Ang II increased CM-H2DCFDA fluorescence, and this was inhibited by catalase (350 U/mL), indicating that the fluorescence signal was derived predominantly from H2O2. Ang II dose-dependently increased H2O2 production (Emax=57.6±1.7 nmol/L, pD2=7.7±0.06) and PLD activation (Emax=207±3.3% of control, pD2=7.7±0.5). H2O2 effects were evident within 1 hour, and maximal PLD activation occurred within 40 minutes after stimulation. DPI inhibited (P<0.01) Ang II–stimulated responses. PLD inhibition significantly attenuated (P<0.05) Ang II–elicited H2O2 production (Emax=29±5 nmol/L). DPI and sphinganine inhibited Ang II–induced DNA and protein synthesis. These data indicate that in vascular smooth muscle cells from human peripheral resistance arteries, Ang II increases H2O2 generation via PLD-dependent, NADH/NADPH oxidase–sensitive pathways. These cascades may function as second messengers in long-term Ang II–mediated growth-signaling events.
Key Words: oxidative stress • superoxide anions • intracellular signaling • vascular hypertrophy
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The multiple actions of Ang II are mediated via highly complex intracellular signaling pathways that are stimulated after binding of the peptide to its cell-surface receptors.1 The signaling processes are multiphasic, with distinct temporal characteristics.2 Ang II–induced activation of phospholipase C characteristically occurs within seconds, resulting in increased intracellular free Ca2+ concentration and rapid vascular contraction,3 4 whereas activation of signaling pathways mediating protein synthesis and cell growth are delayed, occurring within minutes or hours after Ang II stimulation.2 5 Although the intracellular signaling events underlying Ang II–induced growth are not completely understood, there is increasing evidence suggesting that generation of reactive oxygen species (ROS), such as superoxide anion (·O2-), hydrogen peroxide (H2O2), and the reactive hydroxyl radical (·OH), may be fundamental in the mitogenic response to this peptide.6 8
The major source of ·O2- in cardiovascular cells is NADH/NADPH oxidase,9 12 which transfers electrons from NADH or NADPH to molecular oxygen, producing ·O2-. The ·O2- that is generated by NADH/NADPH oxidase is converted by superoxide dismutase to H2O2, which is scavenged by catalase or by peroxidases.13 ·O2- and H2O2 stimulate vascular smooth muscle cell (VSMC) hyperplasia and hypertrophy.6 9 14 These effects are associated with growth-related events such as intracellular alkalinization, increased intracellular free Ca2+ concentration, MAP kinase activation, and induction of proto-oncogene expression.6 15 17 Furthermore, antioxidants inhibit cell growth and trigger apoptosis, which implies that a basal level of oxidant stress is necessary for normal cell growth.18 19 Vascular tissue is constantly exposed to endogenous and exogenous oxidants, which, if unscavenged, may lead to cellular proliferation. ROS concentrations are increased in atherosclerosis, neointimal formation, and hypertension.20 22 In Ang II–induced but not catecholamine-induced hypertension, aortic superoxide is increased, which suggests that Ang II–induced effects in hypertension are mediated in part through oxidative stress.23 24
Ang II–stimulated growth of VSMCs has an essential redox-sensitive component that is mediated by activation of mitogen-activated protein (MAP) kinase–dependent signaling pathways.25 The major MAP kinase targets of H2O2 are ERK-5 and p38.26 27 Although some of the downstream targets of ·O2- and H2O2 have been identified, the upstream regulators linking Ang II to the NADH/NADPH oxidase–dependent signaling pathways that generate ROS are still unclear. A potential candidate is phospholipase D (PLD), which hydrolyzes phosphatidylcholine to choline and phosphatidic acid.27 Ang II activates PLD in rat VSMCs and stimulates production of phosphatidic acid in cardiac fibroblasts.28 30 Phosphatidic acid induces protein synthesis and hypertrophy and increases expression of c-fos and c-myc mRNA.31 32 In addition, phosphatidic acid stimulates NADPH oxidase–dependent ·O2- formation in neutrophils and VSMCs.9 33 Thus, activation of PLD may be an important mechanism by which Ang II stimulates production of ROS in the vasculature.
In the present study, we examined whether Ang II activates redox-sensitive pathways through NADH/NADPH oxidase and assessed the mitogenic role of oxidative stress in VSMCs from human peripheral resistance arteries, the vessels that play a critical role in blood pressure regulation. Furthermore, we investigated the putative role of PLD as a regulator of Ang II–induced oxidative stress. Data from our study demonstrate that Ang II stimulates production of reactive oxygen molecules, primarily H2O2, via NADH/NADPH oxidase. These responses are mediated via PLD-dependent signaling pathways, which play a critical role in Ang II–stimulated DNA and protein synthesis. Our findings suggest that PLD activation may be an important upstream modulator of Ang II–stimulated oxidative stress in human VSMCs.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cell Culture
The study was approved by the Ethics Committee of the Clinical Research Institute of Montreal. Written informed consent to participate in the study was obtained from each subject. Four normotensive, healthy men (25 to 50 years old) were recruited. Gluteal biopsies of subcutaneous fat measuring 1.0x0.5x0.5 cm3 were obtained under local anesthetic. Small arteries were dissected from gluteal fat as previously described.34 VSMCs were isolated and characterized as described in detail previously.35 Cells were seeded onto round glass coverslips in plastic 6-well dishes and in a 15-mL plastic flask. Cells were grown to confluence, at which stage those on coverslips were used for experiments and those in the flask were trypsinized and subcultured. Before experimentation, cells were rendered quiescent by serum deprivation and maintenance in a serum-free medium for 30 to 36 hours. Only primary and low-passage cells (passages 1 to 4) were studied.
Measurement of Intracellular ROS
Ang II–induced generation of ROS was measured with the
fluorescent dye 5-(and
6)-chloromethyl-2',7'-dichlorodihydrofluorescein
diacetate (CM-H2DCFDA) (Molecular Probes, Inc),
which is a chloromethyl derivative of
dichlorodihydrofluorescein
diacetate (DCF-DA) that exhibits much better retention in living cells
than DCF-DA.36 Cells were washed in modified Hanks'
buffered saline containing (in mmol/L) NaCl 137,
NaHCO3 4.2, NaHPO4 3, KCl
5.4, KH2PO4 0.4,
CaCl2 1.3, MgCl2 0.5,
MgSO4 0.8, glucose 10, and HEPES 5 (pH 7.4). The
cells were washed with Hanks' buffer and loaded with
CM-H2DCFDA (8 µmol/L), which was dissolved
in dimethyl sulfoxide and incubated for 30 minutes at room
temperature.
CM-H2DCFDA fluorescence was measured by fluorescence digital imaging with an Axiovert 135 inverted microscope (x40 oil immersion objective) and Attofluor Digital Fluorescence System (Zeiss) with an excitatory wavelength of 495 nm. Video images of fluorescence at a 520-nm emission wavelength were obtained by use of an intensified CCD camera system (Zeiss) with the output digitized to a resolution of 512x480 pixels. Although CM-H2DCFDA reacts with intracellular H2O2 as well as with other peroxides, the fluorescence signal elicited by Ang II appears to be derived primarily from H2O2, because catalase (350 U/mL) preincubation for 2 hours eliminated Ang II–induced fluorescence. These data confirm those previously reported.9 14 Intracellular H2O2 was calculated from a calibration curve obtained by determining the fluorescence intensity of H2O2 at various concentrations. The calibration curve was linear between 1 and 80 nmol/L (r=0.98, n=5). Generation of ROS was measured in unstimulated cells and in cells exposed to increasing concentrations (10-11 to 10-5 mol/L) of Ang II in the absence and presence of 10-5 mol/L diphenylene iodonium (DPI), a flavoprotein inhibitor,37 or the PLD inhibitor D-erythro-sphingosine, dihydro (sphinganine).38 Cells were pretreated with inhibitors for 15 to 20 minutes before addition of Ang II. Cells were used for single experiments only.
PLD Assay
PLD activity was determined by the transphosphatidylation
method, in which the incorporation of metabolically
prelabeled phosphatidyl moieties into phosphatidylethanol (PEt) is
measured.39 For PLD assays, cells were subcultured into
6-well plates and studied at 
70% confluence. To label VSMC
phospholipids, cells were incubated for 24 hours with
[3H]myristate (2 µCi/mL). Cells were
washed in warmed buffer containing (in mmol/L)
CaCl2 1.26, MgCl2 0.5,
MgSO4 0.4, KCl 5.37, NaCl 137,
NaHCO3 4.2,
NaH2PO4 0.35, HEPES 10 (pH
7.4), and glucose 10, and 1% BSA. Cells were then incubated in buffer
containing 1% ethanol for 10 minutes at 37°C, followed by addition
of Ang II (10-11 to 10-6
mol/L) for various times (1 to 60 minutes). In some experiments, cells
were pretreated for 20 to 30 minutes with sphinganine
(10-5 mol/L) before addition of Ang II. The
experiments were terminated by aspiration of the treatment buffer,
placement of the cells on ice, and addition of ice-cold methanol (0.5
mL) to each well. Lipids were extracted according to Wakelam et
al39 and analyzed by thin-layer
chromatography on Silica Gel LK6D TLC plates (Whatman).
The plates were developed by use of the solvent system of
2,2,4-trimethylpentane (isooctane):ethyl acetate:acetic acid:water
(50:110:20:100 by volume). PEt was visualized by use of iodine vapors
and identified by the position of authentic standards. These areas were
scraped from the plates into scintillation vials containing 0.5 mL
H2O scintillant and incubated at room temperature
for 24 hours to allow complete extraction.
Determination of DNA and Protein Synthesis
Cells were seeded, at an initial concentration of
1x105 cells/mL, into 24-well multiwell plates.
DNA synthesis, which was evaluated by measurement of incorporation of
[3H]thymidine into DNA, was considered to be a
marker of hyperplasia, and protein synthesis, which was determined by
measurement of [3H]leucine incorporation, was
considered to be a marker of hypertrophy. Quiescent cells
were stimulated for 30 hours with increasing concentrations of Ang II.
To determine whether oxidase inhibition influences Ang II–induced
growth, cells were exposed to DPI at the same time that Ang II was
added. To assess the role of PLD-dependent pathways, cells were treated
with sphinganine (10-5 mol/L) at the same time
that Ang II was added. [3H]thymidine and
[3H]leucine incorporation was measured as
previously described.35 For protein synthesis studies, 2
µCi/mL [3H]leucine was added at the same time
as Ang II. For [3H]thymidine studies, 5
µCi/mL [3H]thymidine was added to Ang
II–stimulated cells and incubated for 4 hours.
Data Analysis
Ang II–stimulated PLD and growth effects were determined as the
percentage increase over control, with the control normalized to 100%.
Each experiment was performed 
3 times. Results are presented
as mean±SEM and compared by ANOVA for repeated measures.
Tukey-Kramer's correction was used to compensate for multiple testing.
Concentration-response curves were fitted by nonlinear regression, and
the concentration, in mol/L, giving 50% response
(EC50) was determined and
pD2 calculated as -log
EC50. A value of P<0.05 was
considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Effects of Ang II on Intracellular Generation of ROS
Ang II significantly increased CH-H2DCFDA fluorescence (Figure 1). Maximal responses were evident within 1 hour of addition of Ang II (Figure 1), and responses were sustained for up to 4 hours. To determine whether H2O2 is the source of the fluorescence, cells were preincubated with catalase, an enzyme that specifically metabolizes H2O2 to H2O and O2. Catalase completely blocked the Ang II–stimulated increase in DCF-DA fluorescence, suggesting that intracellular H2O2 is primarily responsible for the fluorescence signal (Figure 1). These data are in agreement with previously published findings in catalase-treated VSMCs and in catalase-transfected cells.9 14 Ang II induced a dose-dependent increase in intracellular H2O2 with maximal fluorescence corresponding to 57.6±1.7 nmol/L (pD2=7.7±0.06) (Figure 2). To determine whether NADH/NADPH oxidase is the source of Ang II–generated H2O2, cells were exposed to DPI. DPI completely inhibited Ang II–stimulated responses (Figures 1 and 2), indicating that a flavin-containing enzyme, such as NADH/NADPH oxidase, is the source for intracellular H2O2.
|
|
PLD Activity
VSMCs prelabeled with
[3H]myristate were exposed to Ang II in
the presence of 1% ethanol. Under these conditions, PLD
catalyzes the conversion of [3H]phospholipids
to [3H]phosphatidic acid and the specific
transphosphatidylation of [3H]phospholipids to
[3H]PEt. Ang II induced a slow and sustained
increase in PEt formation. Ang II at 10-7 mol/L
elicited a maximal response at 20 minutes that was sustained for up to
60 minutes after addition of Ang II (Figure 3, top). The course of PLD activation was
temporally associated with production of ROS, which peaked at
about 40 to 50 minutes (Figure 1). Ang II dose-dependently
increased formation of PEt (Emax=207±3.3% of
control, pD2=7.8±0.5) (Figure 3, bottom).
These effects were significantly inhibited when cells were exposed to
sphinganine (Figure 3, bottom).
|
Role of PLD–Dependent Signaling Pathways on Ang II–Generated
ROS
To determine whether PLD influences Ang II–stimulated
production of ROS, cells were pretreated with sphinganine,
which we found to inhibit Ang II–induced PLD activation (Figure 3). Sphinganine did not alter basal fluorescence but
significantly attenuated Ang II–stimulated formation of
H2O2 (Figure 4). These results suggest that
PLD-dependent pathways play a role in Ang II–stimulated oxidative
stress. To examine the possibility that Ang II generates ROS via
phosphatidic acid, we assessed the direct effects of phosphatidic acid
on H2O2 production.
Phosphatidic acid significantly increased fluorescence (Figure 5). At 1.5 and 50 µmol/L,
phosphatidic acid increased
H2O2 to 44±4.9 and 81±6.3
nmol/L, respectively. Peak fluorescence signals were obtained
within 20 minutes after addition of phosphatidic acid.
|
|
To exclude the possibility that sphinganine-elicited effects may be mediated via PLD-independent pathways or through direct scavenging of H2O2, we examined the oxidative effects of Ang II in cells pretreated with sphinganine that were then exposed to phosphatidic acid (1 µmol/L). Sphinganine inhibited Ang II–elicited production of H2O2 (Figure 6). Addition of phosphatidic acid resulted in a significant increase (P<0.05) in the generation of H2O2 (Figure 6). These results suggest that in our experimental paradigm, sphinganine-induced effects on Ang II–stimulated production of oxygen species are PLD-dependent.
|
An important downstream effector of PLD and phosphatidic acid is diacylglycerol (DAG), which activates protein kinase C (PKC). To assess whether PKC influences Ang II–stimulated oxidative stress in human VSMCs, the effects of 2 selective PKC inhibitors, calphostin C and chelerythrine chloride,40 on Ang II–induced generation of H2O2 were determined. Cells were preincubated with either PKC inhibitor (10-5 mol/L) for 20 minutes before addition of Ang II (10-7 mol/L). Ang II–induced formation of H2O2 was significantly reduced (P<0.05), but not completely abolished, by calphostin C (45.5±2.5 versus 59±4.0 nmol/L, calphostin C+Ang II versus Ang II alone) and chelerythrine chloride (38.6±6.3 versus 59±4.0 nmol/L, chelerythrine+Ang II versus Ang II alone).
Role of PLD and H2O2 in Ang II–Stimulated
DNA and Protein Synthesis
Ang II dose-dependently increased
[3H]thymidine and
[3H]leucine incorporation in human VSMCs
(Figure 7). To assess the role of
oxidative stress in Ang II–stimulated growth, cells were exposed to
DPI. DPI at a concentration of 10-4 mol/L, which
was used by other investigators,9 12 was toxic to the
cells in the present study. At a concentration of
10-5 mol/L, however, cells remained viable for
24 to 30 hours after addition of DPI, as determined morphologically and
by trypan blue exclusion. DPI slightly reduced basal
[3H]thymidine and
[3H]leucine incorporation and significantly
blocked Ang II–induced DNA and protein synthesis (Figure 7),
indicating an important role for ROS in Ang II–induced growth. To
evaluate the role of PLD-dependent pathways, cells were exposed to
sphinganine, which significantly reduced Ang II–stimulated DNA and
protein synthesis (Figure 7). Sphinganine alone did not alter
basal [3H]thymidine or
[3H]leucine incorporation.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The major findings of the present study indicate that Ang II–induced activation of PLD and generation of ROS are temporally associated, that the major intracellular oxygen free radical produced by Ang II is H2O2, and that inhibition of PLD and NADH/NADPH oxidase attenuates Ang II–stimulated production of H2O2 and DNA and protein synthesis. We also demonstrate that PKC, a downstream effector of PLD-dependent signaling pathways, regulates, in part, Ang II–induced formation of oxygen species. These findings suggest that PLD is an important modulator of Ang II–stimulated oxidative stress and is critical in redox-sensitive growth in human VSMCs.
Our results demonstrating the potent oxidant-producing effects of Ang
II support findings in rat aortic cells.6 9 Unlike
previous investigations that used DCF-DA as the fluorescent
probe, we used CM-H2DCFDA, a chloromethyl
derivative of H2DCFDA that exhibits much better
retention in living cells. CM-H2DCFDA diffuses
passively into cells, where its acetate groups are cleaved by
intracellular esterases and its thiol-reactive chloromethyl group
reacts with intracellular thiols. Further oxidation yields a
fluorescent adduct that is trapped within the cell, thus
facilitating long-term studies. Using this probe, we were able to
monitor fluorescence for up to 90 minutes without occurrence of
photo-bleaching. We believe that this is the first study to
continuously track Ang II–induced CM-H2DCFDA
fluorescence in human VSMCs, which allowed us to gain insight
into the temporal events associated with intracellular generation of
ROS. Ang II induced a slow and sustained increase in
fluorescence that plateaued at 40 to 50 minutes after
addition of Ang II. These results are in contrast to others that
reported an acute peak response within 1 minute, followed by maximum
fluorescence at 4 hours after Ang II
stimulation.9 26 In these studies, 1 time point was
assessed and less stable fluorescent probes were used. The
delayed and sustained increase in
H2O2 suggests that
oxidative stress probably contributes to long-term signaling events
associated with Ang II, such as protein synthesis and cell growth. The
growth-stimulating effects of
·O2- and
H2O2 have been documented
in various cell types. H2O2
stimulates VSMC proliferation, NADH/NADPH oxidase inhibition reduces
Ang II–stimulated hypertrophy, and VSMC treatment with
antioxidants induces apoptosis.18 19 Our findings
in human VSMCs support a redox-sensitive growth effect of Ang II. The
mechanisms through which ROS mediate growth appear to be linked to
activation of ERK5 and p38 MAP kinase, which are redox-sensitive
kinases. ERK 5 phosphorylates the transcription factor
MCEF2C, and p38 MAP kinase activates ATF-2 C/EPT-homologous
protein, MAPKAP kinase 2/3 heat-shock proteins, and the transcription
factor MEF2C, which is essential for proper growth and development of
cardiac and vascular muscle.26 27 41
In the present study, DPI inhibited both Ang II–stimulated
formation of H2O2 and DNA
and protein synthesis, indicating that the major source of oxidative
stress in human VSMCs is an NADH/NADPH oxidase that seems to be
critical in Ang II modulation of cell growth. These findings are
similar to those in endothelial cells and VSMCs from
rats.9 12 Although it is well established that Ang
II–stimulated ROS derive mainly from NADH/NADPH oxidase, the
mechanisms through which Ang II activates the cell
membrane–associated enzyme are unclear. In the present study, we
questioned whether PLD may be a potential upstream regulator of Ang
II–stimulated oxidative stress. This hypothesis is based on the
following: in rat cells, (1) Ang II receptor coupling to PLD is
mediated by the ß
subunits of heterotrimeric G proteins; (2) Ang
II activates PLD, which results in production of
phosphatidic acid that is mitogenic, and induces expression
of proto-oncogenes; and (3) phosphatidic acid directly
activates neutrophil and VSMC NADH/NADPH
oxidase.28 32 42 In our study, Ang II induced a
dose-dependent increase in PLD activity that was blocked by the PLD
inhibitor sphinganine. The time course for PLD activation
was delayed and sustained, with maximal activation occurring at 20 to
40 minutes. Interestingly, the course of PLD activation was temporally
associated with generation of ROS, suggesting a possible link between
PLD activity and production of oxygen free radicals. To further
support this relationship, we demonstrated that inhibition of PLD by
sphinganine significantly reduced Ang II–mediated increase in
CM-H2DCFDA fluorescence as well as Ang
II–stimulated [3H]thymidine and
[3H]leucine incorporation. These results
suggest that PLD-dependent signaling pathways influence Ang
II–elicited oxidative stress and DNA and protein synthesis. To assess
whether the major product of PLD activation, phosphatidic acid,
could be a possible mediator of oxygen free radicals, we determined the
direct actions of phosphatidic acid on
H2O2 production.
Phosphatidic acid had a potent stimulatory effect on
H2O2 formation. Thus,
phosphatidic acid may be a direct link between Ang II and NADH/NADPH
oxidase–generating ROS.
To exclude the possibility that sphinganine-elicited effects may be mediated via PLD-independent pathways or through direct scavenging of H2O2, we examined the oxidative effects of Ang II in cells pretreated with sphinganine that were then exposed to phosphatidic acid. Sphinganine blocked Ang II–stimulated formation of H2O2. When phosphatidic acid was added, there was a slow and sustained increase in H2O2 generation, suggesting that sphinganine-induced effects are mediated primarily via PLD.
It is also possible that DAG, an important product of phosphatidic acid and inducer of PKC activation, could activate redox-sensitive pathways.27 To address this aspect, we examined the oxidative effects of Ang II in the presence of 2 potent and selective PKC inhibitors, calphostin C and chelerythrine chloride.40 PKC inhibition significantly attenuated, but did not completely abolish, H2O2 production, suggesting that Ang II–mediated oxidative stress is mediated in part via PKC–dependent pathways. These data are supported by previous studies that demonstrated that DAG is an endogenous activator of NADPH oxidase.43
In conclusion, Ang II induces a PLD-dependent, NADH/NADPH oxidase–sensitive increase in the generation of ROS that is pivotal in oxidative stress–stimulated DNA and protein synthesis. These data identify PLD as a major component of the intracellular signaling pathways that regulate Ang II production of ROS in human VSMCs.
|
Acknowledgments |
|---|
This study was supported by grant MT 14080 and a group grant to the Multidisciplinary Research Group on Hypertension of the Medical Research Council of Canada. L.-Y. Deng is thanked for her technical assistance.
Received May 9, 1999; first decision July 16, 1999; accepted August 2, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Matsusaka T, Ichikawa I. Biological functions of angiotensin and its receptors. Annu Rev Physiol. 1997;59:395–412.[Medline] [Order article via Infotrieve]
2. Griendling KK, Ushio-Fukai M, Lassègue B, Alexander RW. Angiotensin II signaling in vascular smooth muscle: new concepts. Hypertension. 1997;29(pt 2):366–373.
3.
Touyz RM, Schiffrin EL. Angiotensin II
regulates vascular smooth muscle cell pH, contraction and growth via
tyrosine-kinase dependent signaling pathways Hypertension.. 1997;30:222–229.
4. Griendling KK, Tsuda T, Berk BC, Alexander RW. Angiotensin II stimulation of vascular smooth muscle. J Cardiovasc Pharmacol. 1989;14(suppl 6):S27–S33.
5.
Berk BC, Corson MA. Angiotensin II signal
transduction in vascular smooth muscle: role of tyrosine kinases.
Circ Res. 1997;80:607–616.
6.
Rao GN, Berk BC. Active oxygen species stimulate
vascular smooth muscle cell growth and proto-oncogene expression.
Circ Res. 1992;70:593–599.
7.
Baas AS, Berk BC. Differential activation of
mitogen-activated protein kinases by
H2O2 and
O2- in vascular smooth muscle
cells. Circ Res. 1995;77:29–36.
8.
Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N,
Griendling KK. p22phox is a critical component of the
superoxide-generating NADH/NADPH oxidase system and regulates
angiotensin II-induced hypertrophy in vascular
smooth muscle cells. J Biol Chem. 1996;271:23317–23321.
9.
Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A,
Harrison DG, Taylor WR, Griendling KK. Role of NADH/NADPH
oxidase-derived H2O2 in
angiotensin II–induced vascular hypertrophy.
Hypertension. 1998;32:488–495.
10.
Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen
JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm
M, Meinertz T, Munzel T. Increased NADH-oxidase–mediated superoxide
production in the early stages of
atherosclerosis: evidence for involvement of the
renin-angiotensin system. Circulation. 1999;99:2027–2033.
11.
Al-Mehdi AB, Zhao G, Dodia C, Tozawa K, Costa K,
Muzykantov V, Ross C, Blecha F, Dinauer M, Fisher AB.
Endothelial NADPH oxidase as the source of oxidants in
lungs exposed to ischemia or high K+.
Circ Res. 1998;83:730–737.
12.
Griendling KK, Miniere CA, Ollerenshaw JD, Alexander
RW. Angiotensin II stimulates NADH and NADPH oxidase
activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–1148.
13.
Fridovich I. Superoxide anion radical, superoxide
dismutases, and related matters. J Biol Chem. 1997;272:18515–18517.
14.
Lu G, Greene EL, Nagai T, Egan BM. Reactive oxygen
species are critical in the oleic acid–mediated mitogenic
signaling pathway in vascular smooth muscle cells.
Hypertension. 1998;32:1003–1010.
15.
Hu Q, Corda S, Zweier JL, Capoggrossi MC, Ziegelstein
RC. Hydrogen peroxide induces intracellular calcium
oscillations in human aortic endothelial
cells. Circulation. 1998;97:268–275.
16.
Puri PL, Avantaggiati ML, Burgio VL, Chirillo P,
Collepardo D, Natoli G, Balsano C, Levrero M. Reactive oxygen
intermediates mediate angiotensin II-induced
c-Jun, c-Fos heterodimer DNA binding activity and
proliferative hypertrophic responses in myogenic cells. J
Biol Chem. 1995;270:22129–22134.
17.
Sabri A, Byron KL, Samarel AM, Bell J, Lucchesi PA.
Hydrogen peroxide activates mitogen-activated protein
kinases and Na+/H+ exchange
in neonatal rat cardiac myocytes. Circ Res. 1998;82:1053–1062.
18.
Tsai J-C, Jain M, Hsieh C-M, Lee WS, Yoshizumi M,
Patterson C, Perrella MA, Cooke C, Wang H, Haber E, Schlegel R, Lee ME.
Induction of apoptosis by pyrrolidinedithiocarbamate and
N-acetylcysteine in vascular smooth muscle cells. J Biol
Chem. 1996;271:3667–3670.
19. Kaal EC, Veldman H, Sodaar P, Joosten EA, Dop Bar PR. Oxidant treatment causes a dose-dependent phenotype of apoptosis in cultured motoneurons. J Neurosci Res. 1998;54:778–786.[Medline] [Order article via Infotrieve]
20. Griendling KK, Alexander RW. Oxidative stress and cardiovascular disease. Circulation. 1997;96:3264–3265.
21.
Fukai T, Ishiizaka N, Rajaggopalan S, Laursen JB,
Capers Q, Taylor WR, Harrison DG, de Leon H, Wilcox JN, Griendling KK.
p22phox mRNA expression and NADH/NADPH oxidase activity are increased
in aortas from hypertensive rats. Circ Res. 1997;80:45–51.
22. Abe J-l, Berk BC. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc Med. 1998;8:59–64.
23.
Laursen JB, Rajagopalan S, Galis Z, Tarpet M, Freeman
BA, Harrison DG. Role of superoxide in angiotensin
II–induced but not catecholamine-induced hypertension.
Circulation. 1997;95:588–593.
24. Rajagopalan S, Kurz S, Múnzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
25. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997;9:180–186.[Medline] [Order article via Infotrieve]
26.
Ushio-Fukai M, Alexander RW, Akers M, Griendling KK.
p38 mitogen-activated protein kinase is a critical component of
the redox-sensitive signaling pathways activated by
angiotensin II: role in vascular smooth muscle cell
hypertrophy. J Biol Chem. 1998;273:15022–15029.
27. Abe J, Kusuhara M, Ulevitch RJ, Berk BC, Lee JD. Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase. J Biol Chem. 1996;273:16586–16590.
28. Gomez-Cambronero J, Keire P. Phospholipase D: a novel major player in signal transduction. Cell Signal. 1998;10:387–397.[Medline] [Order article via Infotrieve]
29. Dhalla NS, Xu Y-J, Sheu S-S, Tappia PS, Panagia V. Phosphatidic acid: a potential signal transducer for cardiac hypertrophy. J Mol Cell Cardiol. 1997;29:2865–2871.[Medline] [Order article via Infotrieve]
30. Freeman EJ, Chisolm GM, Tallant EA. Role of calcium and protein kinase C in the activation of phospholipase D by angiotensin II in vascular smooth muscle cells. Arch Biochem Biophys. 1995;319:84–92.[Medline] [Order article via Infotrieve]
31.
Knauss TC, Jaffer FE, Abboud HE. Phosphatidic acid
modulates DNA synthesis, phospholipase C and platelet-derived
growth factor mRNAs in cultured mesangial cells.
J Biol Chem. 1990;265:14457–14463.
32. Booz GW, Taher MM, Baker KM, Singer HA. Angiotensin II induces phosphatidic acid formation in neonatal rat cardiac fibroblasts: evaluation of the role of phosphatidic acid. J Mol Cell Biochem. 1994;141:135–143.
33.
Bellavite P, Corso F, Dusi S, Grzeskowiak M,
Della-Bianca V, Rossi F. Activation of NADPH-dependent superoxide
production in plasma membrane extracts of pig neutrophils by
phosphatidic acid. J Biol Chem. 1988;263:8210–8214.
34.
Schiffrin EL, Deng LY, Larochelle P. Effects of a
ß-blocker or a converting enzyme inhibitor on resistance
arteries in essential hypertension. Hypertension. 1994;23:83–91.
35. Touyz RM, Deng L-Y, He G, Wu X-H, Schiffrin El. Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: role of extracellular signal-regulated kinases. J Hypertens. 1999;17:907–917.[Medline] [Order article via Infotrieve]
36. Haugland RP. Handbook of Fluorescent Probes and Research Chemicals: Molecular Probes. 6th ed. Eugene, Ore: Molecular Probes Inc; 1996:491–492.
37.
Majander A, Finel M, Wikstrom M. Diphenyleneiodinium
inhibits reduction of iron-sulfur clusters in the mitochondrial
NADH-ubiquinone oxidoreductase. J Biol Chem. 1994;269:21037–21042.
38. Franson RC, Harris LK, Ghosh SS, Rosenthal MD. Sphingolipid metabolism and signal transduction: inhibition of in vitro phospholipase activity by sphingosine. Biochim Biophys Acta. 1992;1136:169–174.[Medline] [Order article via Infotrieve]
39. Wakelam MJO, Hodgkin M, Martin A. The measurement of phospholipase D-linked signaling in cells. In: Kendall DA, Hill SJ, eds. Methods in Molecular Biology, Vol 41: Signal Transduction Protocols. Totowa, NJ: Humana Press Inc; 1995:271–278.
40.
Jarvis WD, Turner AJ, Povirk LF, Traylor RS, Grant S.
Induction of apoptotic DNA fragmentation and cell death in
HL-60 human promyelocytic leukemia cells by pharmacological
inhibitors of protein kinase C. Cancer Res. 1994;54:1707–1714.
41. New L, Han J. The p38 MAP kinase pathway and its biological function. Trends Cardiovasc Med. 1998;8:220–229.[Medline] [Order article via Infotrieve]
42.
Ushio-Fukai M, Alexander RW, Akers M, Lyons PR,
Lassègue B, Griendling KK. Angiotensin II receptor
coupling to phospholipase D is mediated by the ß subunits of
heterotrimeric G proteins in vascular smooth muscle cells. Mol
Pharmacol. 1999;55:142–149.
43.
Burnham DN, Uhlinger DJ, Lambeth JD. Diradylglycerol
synergizes with an anionic amphiphile to activate superoxide
generation and phosphorylation of p47phox in a
cell-free system from human neutrophils. J Biol Chem. 1990;265:17550–17559.
This article has been cited by other articles:
 |
|
 |
|
  J. Xu, S. Wang, Y. Wu, P. Song, and M.-H. Zou Tyrosine Nitration of PA700 Activates the 26S Proteasome to Induce Endothelial Dysfunction in Mice With Angiotensin II-Induced Hypertension Hypertension, September 1, 2009; 54(3): 625 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Siekmeier, T. Grammer, and W. Marz Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 279 - 297. [Abstract] [PDF]
|
|
|
|
 |
|
 K. E. Herbert, Y. Mistry, R. Hastings, T. Poolman, L. Niklason, and B. Williams Angiotensin II-Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways Circ. Res., February 1, 2008; 102(2): 201 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Choi, T. L. Leto, L. Hunyady, K. J. Catt, Y. S. Bae, and S. G. Rhee Mechanism of Angiotensin II-induced Superoxide Production in Cells Reconstituted with Angiotensin Type 1 Receptor and the Components of NADPH Oxidase J. Biol. Chem., January 4, 2008; 283(1): 255 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bechara, X. Wang, H. Chai, P. H. Lin, Q. Yao, and C. Chen Growth-related oncogene-{alpha} induces endothelial dysfunction through oxidative stress and downregulation of eNOS in porcine coronary arteries Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3088 - H3095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Zemse, R. H. P. Hilgers, and R. C. Webb Interleukin-10 counteracts impaired endothelium-dependent relaxation induced by ANG II in murine aortic rings Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3103 - H3108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, T. Shimosawa, H. Matsui, F. Meng, S. C. Supowit, D. J. DiPette, K. Ando, and T. Fujita Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1714 - H1721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Clempus and K. K. Griendling Reactive oxygen species signaling in vascular smooth muscle cells Cardiovasc Res, July 15, 2006; 71(2): 216 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hunyady and K. J. Catt Pleiotropic AT1 Receptor Signaling Pathways Mediating Physiological and Pathogenic Actions of Angiotensin II Mol. Endocrinol., May 1, 2006; 20(5): 953 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ardanaz and P. J. Pagano Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Experimental Biology and Medicine, March 1, 2006; 231(3): 237 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Jalil, A. Perez, M. P. Ocaranza, J. Bargetto, A. Galaz, and S. Lavandero Increased Aortic NADPH Oxidase Activity in Rats With Genetically High Angiotensin-Converting Enzyme Levels Hypertension, December 1, 2005; 46(6): 1362 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Ullian, A. K. Gelasco, W. R. Fitzgibbon, C. N. Beck, and T. A. Morinelli N-Acetylcysteine Decreases Angiotensin II Receptor Binding in Vascular Smooth Muscle Cells J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2346 - 2353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Andresen, K. Shome, E. K. Jackson, and G. G. Romero AT2 receptors cross talk with AT1 receptors through a nitric oxide- and RhoA-dependent mechanism resulting in decreased phospholipase D activity Am J Physiol Renal Physiol, April 1, 2005; 288(4): F763 - F770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Schiffrin and R. M. Touyz Calcium, Magnesium, and Oxidative Stress in Hyperaldosteronism Circulation, February 22, 2005; 111(7): 830 - 831. [Full Text] [PDF]
|
|
|
|
|
|
Z. Yang, L. D. Asico, P. Yu, Z. Wang, J. E. Jones, R.-k. Bai, D. R. Sibley, R. A. Felder, and P. A. Jose D5 dopamine receptor regulation of phospholipase D Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H55 - H61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhang, K. Rhinehart, G. Solis, J. Pittner, W. Lee-Kwon, W. J. Welch, C. S. Wilcox, and T. L. Pallone Chronic ANG II infusion increases NO generation by rat descending vasa recta Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H29 - H36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Williams, J. S. Pollock, and D. M. Pollock Arterial Pressure Response to the Antioxidant Tempol and ETB Receptor Blockade in Rats on a High-Salt Diet Hypertension, November 1, 2004; 44(5): 770 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Boustany, K. Bharadwaj, A. Daugherty, D. R. Brown, D. C. Randall, and L. A. Cassis Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R943 - R949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Endemann and E. L. Schiffrin Endothelial Dysfunction J. Am. Soc. Nephrol., August 1, 2004; 15(8): 1983 - 1992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhang, K. Rhinehart, W. Kwon, E. Weinman, and T. L. Pallone ANG II signaling in vasa recta pericytes by PKC and reactive oxygen species Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H773 - H781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yoshimoto, N. Fukai, R. Sato, T. Sugiyama, N. Ozawa, M. Shichiri, and Y. Hirata Antioxidant Effect of Adrenomedullin on Angiotensin II-Induced Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells Endocrinology, July 1, 2004; 145(7): 3331 - 3337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Andresen, G. G. Romero, and E. K. Jackson AT2 Receptors Attenuate AT1 Receptor-Induced Phospholipase D Activation in Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 425 - 431. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. Du, P. Huang, B. T. Liang, and M. A. Frohman Phospholipase D2 Localizes to the Plasma Membrane and Regulates Angiotensin II Receptor Endocytosis Mol. Biol. Cell, March 1, 2004; 15(3): 1024 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Bleeke, H. Zhang, N. Madamanchi, C. Patterson, and J. E. Faber Catecholamine-Induced Vascular Wall Growth Is Dependent on Generation of Reactive Oxygen Species Circ. Res., January 9, 2004; 94(1): 37 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ritz and V. Haxsen Angiotensin II and Oxidative Stress: An Unholy Alliance J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2985 - 2987. [Full Text] [PDF]
|
|
|
|
|
|
B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Didion and F. M. Faraci Angiotensin II Produces Superoxide-Mediated Impairment of Endothelial Function in Cerebral Arterioles Stroke, August 1, 2003; 34(8): 2038 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Finckenberg, K. Inkinen, J. Ahonen, S. Merasto, M. Louhelainen, H. Vapaatalo, D. Muller, D. Ganten, F. Luft, and E. Mervaala Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways Am. J. Pathol., July 1, 2003; 163(1): 355 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Desideri, M. C. Bravi, M. Tucci, G. Croce, M. C. Marinucci, A. Santucci, E. Alesse, and C. Ferri Angiotensin II Inhibits Endothelial Cell Motility Through an AT1-Dependent Oxidant-Sensitive Decrement of Nitric Oxide Availability Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1218 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Cifuentes and P. J. Pagano c-Src and Smooth Muscle NAD(P)H Oxidase: Assembling a Path to Hypertrophy Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 919 - 921. [Full Text] [PDF]
|
|
|
|
|
|
R.M. Touyz, G. Yao, and E.L. Schiffrin c-Src Induces Phosphorylation and Translocation of p47phox: Role in Superoxide Generation by Angiotensin II in Human Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 981 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Frank, M. Mifune, T. Inagami, M. Ohba, T. Sasaki, S. Higashiyama, P. J. Dempsey, and S. Eguchi Distinct Mechanisms of Receptor and Nonreceptor Tyrosine Kinase Activation by Reactive Oxygen Species in Vascular Smooth Muscle Cells: Role of Metalloprotease and Protein Kinase C-{delta} Mol. Cell. Biol., March 1, 2003; 23(5): 1581 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Muller, E. Shagdarsuren, J.-K. Park, R. Dechend, E. Mervaala, F. Hampich, A. Fiebeler, X. Ju, P. Finckenberg, J. Theuer, et al. Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage Am. J. Pathol., November 1, 2002; 161(5): 1679 - 1693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Seshiah, D. S. Weber, P. Rocic, L. Valppu, Y. Taniyama, and K. K. Griendling Angiotensin II Stimulation of NAD(P)H Oxidase Activity: Upstream Mediators Circ. Res., September 6, 2002; 91(5): 406 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz, X. Chen, F. Tabet, G. Yao, G. He, M. T. Quinn, P. J. Pagano, and E. L. Schiffrin Expression of a Functionally Active gp91phox-Containing Neutrophil-Type NAD(P)H Oxidase in Smooth Muscle Cells From Human Resistance Arteries: Regulation by Angiotensin II Circ. Res., June 14, 2002; 90(11): 1205 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hirota, A. Ichihara, Y. Koura, M. Hayashi, and T. Saruta Phospholipase D Contributes to Transmural Pressure Control of Prorenin Processing in Juxtaglomerular Cell Hypertension, February 1, 2002; 39(2): 363 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz, G. He, M. El Mabrouk, and E. L. Schiffrin p38 MAP Kinase Regulates Vascular Smooth Muscle Cell Collagen Synthesis by Angiotensin II in SHR But Not in WKY Hypertension, February 1, 2001; 37(2): 574 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Luft Workshop: Mechanisms and Cardiovascular Damage in Hypertension Hypertension, February 1, 2001; 37(2): 594 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Thannickal and B. L. Fanburg Reactive oxygen species in cell signaling Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1005 - L1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Griendling, D. Sorescu, B. Lassegue, and M. Ushio-Fukai Modulation of Protein Kinase Activity and Gene Expression by Reactive Oxygen Species and Their Role in Vascular Physiology and Pathophysiology Arterioscler Thromb Vasc Biol, October 1, 2000; 20(10): 2175 - 2183. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||