© 2001 American Heart Association, Inc.
Thrombosis |
Critical Role of Rho-Kinase and MEK/ERK Pathways for Angiotensin II–Induced Plasminogen Activator Inhibitor Type-1 Gene Expression
From the Department of Cardiovascular Medicine (K.T., T.I., T.T., N.I., H.S., A.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan, and the Department of Cardiovascular Medicine (S.F., A.K.), Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
Correspondence to Toshihiro Ichiki, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan. E-mail ichiki{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Abstract—Plasminogen activator inhibitor type-1 (PAI-1) plays an integral role not only in the regulation of fibrinolytic activity but also in the pathogenesis of atherosclerosis and hypertension. We investigated the signaling pathways of angiotensin II (Ang II) leading to PAI-1 gene expression. Ang II increased the PAI-1 mRNA and protein levels in a time- and dose-dependent manner through the Ang II type 1 receptor in vascular smooth muscle cells. PAI-1 gene promoter activity measured by luciferase assay was significantly increased by Ang II. PAI-1 mRNA stability was also increased by Ang II. Ang II–induced PAI-1 mRNA upregulation was inhibited by BAPTA-AM, genistein, and AG1478, suggesting that intracellular calcium, tyrosine kinase, and epidermal growth factor receptor transactivation are involved. Furthermore, PD98059, an inhibitor of extracellular signal–regulated kinase (ERK) kinase (MEK), almost completely suppressed Ang II–induced PAI-1 upregulation. Adenovirus-mediated overexpression of the dominant-negative form of Rho-kinase or Y27632, a Rho-kinase inhibitor, also completely prevented PAI-1 induction by Ang II without affecting Ang II–induced ERK activation. These data suggest that activation of MEK/ERK and Rho-kinase pathways plays a pivotal role in PAI-1 gene upregulation by Ang II. The Rho-kinase pathway may be a novel target to inhibit Ang II signaling, and its inhibition may be useful in the treatment of hypertension as well as atherosclerosis.
Key Words: plasminogen activator inhibitor type-1 • vascular smooth muscle cells • angiotensin II • extracellular signal–regulated kinase • Rho-kinase
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Introduction |
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Plasminogen activator inhibitor type-1 (PAI-1) is the primary inhibitor of tissue-type and urokinase-type plasminogen activators and therefore is considered to play an integral role in the control of the fibrinolytic system.1 Furthermore, a growing body of evidence suggests that PAI-1 plays a crucial role in the development of atherosclerosis2 and neointimal formation after balloon injury.3 PAI-1 levels have been shown to be elevated in patients with hypertension, type 2 diabetes, insulin resistance, and hypertriglyceridemia,4 which are known to accelerate atherosclerosis. Furthermore, it has been shown that PAI-1 expression is upregulated in atherosclerotic lesions.2 An elevation of the plasma PAI-1 level is considered to facilitate fibrin deposition by reducing fibrinolytic activity. In addition, PAI-1 promotes fibrosis of the vessel wall by preventing the activation of matrix metalloproteinase by plasmin.5
Angiotensin II (Ang II) has been implicated in the pathogenesis of atherosclerosis, hypertension, and neointimal formation after balloon injury.6 Ang II causes hypertrophy of vascular smooth muscle cells (VSMCs),7 extracellular matrix production, and the expression of various growth factors.8 Although 2 Ang II receptor isoforms, designated type 1 receptor (AT1-R)9 and type 2 receptor (AT2-R),10 have been cloned, most of the cardiovascular effects are mediated by AT1-R. Ang II has been shown to activate various protein kinase pathways through AT1-R. It is well known that Ang II activates extracellular signal–regulated protein kinase (ERK),11 which is a critical protein kinase for cell proliferation and gene expression, and that epidermal growth factor receptor (EGF-R) transactivation and Src kinase activation by Ang II are required for ERK activation.12 Ang II also activates another class of mitogen-activated protein (MAP) kinases, such as p38 MAP kinase13 and Jun N-terminal kinase (JNK).14 Recently, the Rho family of small GTPase is reported to play an important role in Ang II signaling.15 Rho A and Rho-kinase, one of the target proteins of Rho A, are implicated not only in cytoskeletal organization16 but also in gene expression, including c-fos.17
Although Ang II has been shown to increase PAI-1 production in VSMCs,18 the molecular mechanism responsible for the induction is not clarified. The aim of the present investigation is to clarify the signaling pathways for PAI-1 induction by Ang II. We demonstrated in the present study that Ang II–induced PAI-1 expression was dependent on an AT1-R–mediated increase in the intracellular calcium level, activation of tyrosine kinase, and EGF-R transactivation. Furthermore, the activation of ERK and Rho-kinase pathways plays a pivotal role in the upregulation of PAI-1 gene expression by Ang II. These findings are important pathophysiological implications for the pathogenesis of atherosclerosis, neointimal formation, and hypertension.
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Methods |
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Reagents
Ang II was purchased from the Peptide Institute. PD98059 was obtained from Research Biochemicals International. BSA, genistein, and tyrphostin AG1478 were purchased from Sigma Chemical Co. BAPTA-AM was purchased from Dojindo. Benidipine was obtained from Kyowa Hakko. DMEM and FBS were purchased from GIBCO-BRL. [
-32P]dCTP was purchased from Du-Pont
NEN. CV11974 was obtained from Takeda Chemical Industries, and PD123319
was obtained from Warner-Lambert, Park Davis Co. Y27632 was provided by
Yoshitomi Pharmaceutical Co. Rabbit anti-rat PAI-1 IgG was acquired
from American Diagnostica, and alkaline
phosphatase–conjugated goat anti-rabbit IgG was obtained from New
England Biolabs. A specific antibody against
phosphorylated myosin binding subunit (MBS) of myosin
phosphatase was a gift from Dr Kaibuchi (Nara Institute of Science and
Technology, Nara, Japan). Other chemical reagents were purchased from
WAKO Pure Chemical, unless mentioned
specifically.
Cell Culture
VSMCs were isolated from the thoracic aortas of
Sprague-Dawley rats and maintained as described
previously.19 Passages
between 6 and 12 were used for the experiments.
Northern Blot Analysis
Total RNA was prepared by an acid
guanidinium–phenol–chloroform extraction method, and Northern blot
analysis was performed as described
previously.20 The
radioactivity of hybridized bands of PAI-1 mRNA and of 18S rRNA was
quantified by a MacBAS Bioimage Analyzer (FUJIFILM). An
EcoRI/PstI
(0.6 kb) fragment of a bovine PAI-1 cDNA was used as a
probe.
Western Blot Analysis
Equivalent amounts of protein from conditioned medium
were diluted 1:1 with sample buffer (0.25 mol/L Tris-HCl, pH 6.8, 40%
glycerol, 4% SDS, 20% 2-mercaptoethanol, and 0.01% bromphenol blue)
and loaded on a 10% SDS-polyacrylamide gel. The expression of
PAI-1 in the conditioned media was assayed by Western blot as
previously
described.21
VSMCs were lysed in RIPA buffer (50 mmol/L NaCl, 30 mmol/L sodium pyrophosphate, 50 mmol/L NaF, 5 mmol/L EDTA, 10 mmol/L Tris, pH 7.4, 1% Triton X-100, 1 mmol/L phenylmethylsulfonyl fluoride, 0.2 U/mL aprotinin, 10 mmol/L pepstatin A, and 25 mmol/L leupeptin). The lysates were subjected to 12% SDS-PAGE and transferred to polyvinylidene difluoride membranes (Millipore). The membrane was probed by use of antibodies against phospho-ERK1/2 and ERK1/2 (New England Biolabs) and an enhanced chemoluminescence detection system (Amersham). Phosphorylation of ERK is reported to be correlated with activation.11 Therefore, we used the phosphorylation of ERK as a measure of its activation.
To evaluate Rho-kinase activity, the extent of phosphorylation of MBS (a substrate of Rho-kinase)22 was measured by Western blot analysis with use of a specific antibody against phosphorylated MBS as described above.
Measurement of PAI-1 Gene Promoter
Activity
VSMCs were prepared in a 6-cm tissue culture dish.
After 48 hours, 5 µg of PAI-1
promoter23 (-760
bp)–luciferase fusion DNA construct and 2 µg of LacZ gene driven by
the SV40 promoter-enhancer sequence were introduced to VSMCs by the
DEAE dextran method as previously
described.24 These cells were
cultured in DMEM supplemented with 10% FBS for 24 hours and stimulated
with Ang II
(10-6 mol/L) in
DMEM containing 0.1% BSA for 24 hours. The luciferase activity was
measured and normalized by ß-galactosidase activity as described
previously.19
Infection of Recombinant Adenoviruses
Adenoviruses expressing a dominant-negative mutant of
Rho-kinase (AdD/N RhoK) or bacterial ß-galactosidase (AdLacZ) were
gifts from Dr Kaibuchi (Nara Institute of Science and Technology, Nara,
Japan). AdD/N RhoK expresses the Rho-binding domain of Rho-kinase. The
Rho-binding domain binds to Rho and inhibits Rho-dependent Rho-kinase
activity.25 VSMCs were
incubated with PBS containing adenovirus vector for 2 hours at room
temperature under gentle agitation. Then these cells were washed and
incubated for an additional 2 days under serum-free conditions and used
for the experiments. Multiplicity of infection indicates the amount of
adenovirus per cell added to culture dish.
Statistical Analysis
Statistical analyses of the relative PAI-1
mRNA expression were performed by using 1-way ANOVA and the Fisher test
if appropriate. Degradation of PAI-1 mRNA was analyzed by 2-way
ANOVA. Data are shown as mean±SEM. A value of
P<0.05 was considered to be
significant.
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Results |
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Enhancement of PAI-1 mRNA and Protein Expression by Ang II
We examined the time course of Ang II–induced PAI-1 mRNA expression. A transient increase in PAI-1 mRNA expression by Ang II was observed (Figure 1A
). The expression of PAI-1 mRNA by Ang II was
increased dose-dependently
(Figure 1B). CV11974, a specific AT1-R
antagonist, completely abolished the PAI-1 mRNA induction
by Ang II. However, PD123319, a specific AT2-R
antagonist, showed no effect
(Figure 1B). These results suggest that Ang II increases
PAI-1 mRNA expression through AT1-R. Western
blot analysis showed that PAI-1 protein levels in the
supernatant of VSMCs were increased time-dependently
(Figure 1C) and dose-dependently
(Figure 1D). The increase in PAI-1 protein by Ang II was
inhibited by CV11974 but not by PD123319
(Figure 1D).
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Transcriptional and Posttranscriptional
Regulation of PAI-1 Gene Expression by Ang II
As shown in
Figure 2A, the PAI-1 promoter activity was significantly
increased by Ang II
(10-6 mol/L,
1.4-fold of control), and Ang II significantly increased the stability
of PAI-1 mRNA compared with that of unstimulated cells
(Figure 2B). These data suggest that Ang II upregulates PAI-1
mRNA expression by transcriptional and posttranscriptional mechanisms.
Although treatment with cycloheximide, an inhibitor of
translation, alone resulted in an increase in basal PAI-1 mRNA
expression as reported previously in endothelial
cells,26 Ang II increased
PAI-1 mRNA expression in the presence of cycloheximide (online Figure
I, which can be accessed at http://atvb.ahajournals.org). These data
suggest that this process does not require de novo protein
synthesis.
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MEK/ERK Pathway Was Crucial in Ang II–Induced
PAI-1 Upregulation
Next, we examined the Ang II signaling
responsible for PAI-1 gene expression. Although pretreatment with
genistein, a tyrosine kinase inhibitor, or PD98059, an ERK
kinase (MEK) inhibitor, slightly decreased basal PAI-1 mRNA
expression, these compounds almost completely suppressed Ang
II–induced PAI-1 mRNA upregulation
(Figure 3). In contrast, SB203580, a p38 MAP kinase
inhibitor, did not affect basal and Ang II-stimulated PAI-1
mRNA upregulation
(Figure 3). These data suggest that tyrosine kinase and
MEK/ERK pathways rather than the p38 MAP kinase pathway are crucial in
Ang II–induced PAI-1 gene upregulation.
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Protein kinase C (PKC) activation has been shown to
enhance PAI-1 production in several cell
lines.27 We examined the
effect of 2 different PKC inhibitors on Ang II–induced
PAI-1 mRNA expression. Although pretreatment with GF109203X or
calphostin C slightly affected basal expression of PAI-1 mRNA, Ang
II–induced upregulation of PAI-1 mRNA was not inhibited by these
inhibitors (online Figure II, which can be accessed online
at http://atvb.ahajournals.org). These data suggest that the PKC
pathway does not play a dominant role in Ang II–induced PAI-1 mRNA
upregulation.
Roles of Intracellular Calcium and EGF-R
Transactivation for Ang II–Induced PAI-1 Upregulation
BAPTA-AM, an intracellular calcium chelator, completely
inhibited Ang II–induced PAI-1 mRNA expression, but benidipine, a
calcium channel blocker, did not
(Figure 4A). These results suggest that Ang II
activates PAI-1 gene expression through an intracellular
calcium-dependent pathway. Next, we examined the effect of tyrphostin
AG1478, a specific EGF-R inhibitor, on Ang II–induced
PAI-1 upregulation. Although AG1478 alone slightly decreased basal
PAI-1 mRNA levels, AG1478 completely abrogated Ang II–induced PAI-1
mRNA upregulation
(Figure 4B), suggesting that EGF-R transactivation is
essential for this process.
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Critical Role of Rho-Kinase Pathway for Ang
II–Induced PAI-1 Upregulation
Y27632, a Rho-kinase inhibitor, almost
completely suppressed Ang II–induced PAI-1 upregulation
(10-5 mol/L,
Figure 5A). To exclude the possible nonspecific effect of
Y27632, we took an advantage of AdD/N RhoK, which specifically inhibits
the Rho-kinase pathway.25
Although Ang II–induced PAI-1 gene expression was not inhibited by
infection of AdLacZ, it was almost completely abrogated by infection of
AdD/N RhoK in a multiplicity-of-infection–dependent manner
(Figure 5B). These findings suggest that the Rho-kinase
pathway is important for Ang II–induced PAI-1 upregulation in
VSMCs.
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It has previously been reported that Rho A activation
decreases endothelial NO synthase mRNA
stability.28 We examined
whether activation of Rho-kinase would affect the mRNA stability of
PAI-1. As shown in
Figure 2B, blockade of Rho-kinase by Y27632 partially
reversed the Ang II–induced stabilization of PAI-1 mRNA. This result
suggests that Ang II–induced Rho-kinase activation may be partially
responsible for the stabilization process of PAI-1
mRNA.
The Relationship of MEK/ERK and
Rho-Kinase
To clarify the relationship between MEK/ERK and
Rho-kinase, we examined whether the Rho-kinase pathway was involved in
Ang II–induced ERK activation. Ang II–induced ERK1/2
phosphorylation was inhibited by PD98059 but not by
Y27632
(Figure 6A) or AdD/N RhoK
(Figure 6B). The phosphorylation of MBS,
which reflects the activation of
Rho-kinase,22 was inhibited
by Y27632; however, PD98059 showed no effect
(Figure 6C). These results suggest that MEK/ERK and
Rho-kinase may be independent of each other in the signaling of Ang
II.
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Discussion |
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We demonstrated that Ang II stimulated PAI-1 gene expression through AT1-R in cultured VSMCs. Ang II increased PAI-1 promoter activity and prolonged PAI-1 mRNA half-life. Activation of Rho-kinase and MEK/ERK pathways was crucial in Ang II–induced PAI-1 mRNA upregulation.
Although Ang II enhanced PAI-1 promoter activity only
moderately, Ang II consistently increased the PAI-1 mRNA level
by severalfold
(Figure 1A). The discrepancy between the result of luciferase
assay and that of Northern blot analysis could be explained by
the finding that Ang II significantly prolonged the PAI-1 mRNA
half-life
(Figure 2B). In other words, Ang II increases PAI-1 mRNA
expression at transcriptional and posttranscriptional levels. PAI-1
mRNA was superinduced by cycloheximide (online Figure I). The 3'
untranslated region of PAI-1 mRNA contains AU-rich
elements,29 which is related
to the mRNA instability. Therefore, Ang II may affect the PAI-1 mRNA
stability though these AU-rich sequences.
Activation of calcium-sensitive tyrosine kinase (Pyk2) and transactivation of EGF-R is indispensable for Ang II–induced ERK activation.12 In trying to delineate the signal transduction pathway regulating PAI-1 gene expression by Ang II, we found that ERK activation played a crucial role. As expected from previous reports, inhibition of the upstream signaling of ERK by BAPTA-AM, genistein, or AG1478 abrogated Ang II–induced PAI-1 mRNA expression.
Rho A and Rho-kinase, one of the target proteins of Rho A,
participate not only in cytoskeletal
organization16 but also in
gene expression.17 Ang
II–induced atrial natriuretic peptide (ANP) gene
expression was completely inhibited by
Botulinum C3
exoenzyme,15 which
specifically inactivates Rho
A.30 It has also been
reported that endothelin-induced ANP gene expression is inhibited by
Y27632 as well as the C3 exoenzyme in cardiac
myocytes.31 These data
suggest that the Rho A/Rho-kinase pathway mediates the Ang II–induced
and endothelin-induced ANP gene expression. Our data suggest that the
Rho-kinase pathway also plays an important role in PAI-1 gene
expression by Ang II. The precise molecular mechanism of
Rho-kinase–dependent PAI-1 gene upregulation requires further
investigation. One possible explanation is the interaction between the
Rho A/Rho-kinase and MEK/ERK pathways. A previous report demonstrated
that Rho A was involved in the lysophosphatidic acid–induced ERK
activation in NIH 3T3
cells.32 However, Rho A was
not involved in the Ang II–induced ERK activation in cardiac
myocytes.33 Although we could
not exclude the possibility that Rho A is upstream of ERK in Ang II
signaling, we clearly demonstrated that inhibition of Rho-kinase did
not affect Ang II–induced ERK activation
(Figure 6A and 6B). Furthermore, Ang II–induced Rho-kinase
activation was not inhibited by the blockade of MEK
(Figure 6C). These results suggest that MEK/ERK and
Rho-kinase may be activated separately by Ang II.
Previous reports have suggested that activation of Rho A enhances activator protein-134 and Ets35 transcriptional activity. Because there are some consensus elements, such as activator protein-1 and Ets, in the promoter of PAI-1 gene,23 Ang II activates Rho A15 and may positively regulate PAI-1 gene expression through these elements. A recent report suggests that Rho-kinase directly regulates transcriptional factors, such as serum response factor, in response to activated Rho A.17 Therefore, it is possible that these transcriptional factors are responsible for Ang II–induced PAI-1 upregulation via Rho-kinase activation. Further study is necessary to determine the critical response element of PAI-1 gene promoter and the trans-acting factor.
An increase in PAI-1 level has been considered to be a risk factor for atherothrombotic events.1 Inhibition of PAI-1 action or suppression of PAI-1 production may be novel strategies for the prevention of cardiovascular disease. A growing body of reports suggests the beneficial effects of ACE inhibitors or AT1-R antagonists in the treatment of cardiovascular diseases. Suppression of Ang II–induced PAI-1 upregulation may contribute to the beneficial effects of ACE inhibitors or AT1-R antagonists. The pathophysiological importance of our observation was that inhibition of Rho-kinase blocked Ang II–mediated PAI-1 gene expression. Thus, the Rho-kinase pathway may be a novel target in the inhibition of Ang II signaling, and its inhibition may be useful in the treatment of not only hypertension but also atherosclerosis and neointimal formation.22
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Acknowledgments |
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This study was supported in part by Welfide Medicinal Research Foundation, Osaka, Japan, and grants-in-aid for scientific research from the Ministry of Education, Science, and Culture (Nos. 12877113 and 11770355).
Received August 29, 2000; accepted January 30, 2001.
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M. Ruperez, R. Rodrigues-Diez, L. M. Blanco-Colio, E. Sanchez-Lopez, J. Rodriguez-Vita, V. Esteban, G. Carvajal, J. J. Plaza, J. Egido, and M. Ruiz-Ortega HMG-CoA Reductase Inhibitors Decrease Angiotensin II-Induced Vascular Fibrosis: Role of RhoA/ROCK and MAPK Pathways Hypertension, August 1, 2007; 50(2): 377 - 383. [Abstract] [Full Text] [PDF]
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 S. A. Hamid, H. S. Bower, and G. F. Baxter Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2598 - H2606. [Abstract] [Full Text] [PDF]
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 L. Oliveira, C. M. Costa-Neto, C. R. Nakaie, S. Schreier, S. I. Shimuta, and A. C. M. Paiva The Angiotensin II AT1 Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure Physiol Rev, April 1, 2007; 87(2): 565 - 592. [Abstract] [Full Text] [PDF]
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Y. Mukai, C.-Y. Wang, Y. Rikitake, and J. K. Liao Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1937 - H1942. [Abstract] [Full Text] [PDF]
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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]
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 L. A. Calo, E. Pagnin, M. Mussap, P. A. Davis, and A. Semplicini Rho/Rho-kinase and C-reactive protein relationship in hypertension and atherosclerosis Nephrol. Dial. Transplant., April 1, 2006; 21(4): 1131 - 1132. [Full Text] [PDF]
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 G. Loirand, P. Guerin, and P. Pacaud Rho Kinases in Cardiovascular Physiology and Pathophysiology Circ. Res., February 17, 2006; 98(3): 322 - 334. [Abstract] [Full Text] [PDF]
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 T. Nakakuki, M. Ito, H. Iwasaki, Y. Kureishi, R. Okamoto, N. Moriki, M. Kongo, S. Kato, N. Yamada, N. Isaka, et al. Rho/Rho-Kinase Pathway Contributes to C-Reactive Protein-Induced Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2088 - 2093. [Abstract] [Full Text] [PDF]
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H. Ohtsu, M. Mifune, G. D. Frank, S. Saito, T. Inagami, S. Kim-Mitsuyama, Y. Takuwa, T. Sasaki, J. D. Rothstein, H. Suzuki, et al. Signal-Crosstalk Between Rho/ROCK and c-Jun NH2-Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1831 - 1836. [Abstract] [Full Text] [PDF]
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H. Shimokawa and A. Takeshita Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1767 - 1775. [Abstract] [Full Text] [PDF]
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 Y. Rikitake and J. K. Liao Rho-Kinase Mediates Hyperglycemia-Induced Plasminogen Activator Inhibitor-1 Expression in Vascular Endothelial Cells Circulation, June 21, 2005; 111(24): 3261 - 3268. [Abstract] [Full Text] [PDF]
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 K. Budzyn, P. D. Marley, and C. G. Sobey Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1248 - 1253. [Abstract] [Full Text] [PDF]
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T. Kishi, Y. Hirooka, A. Masumoto, K. Ito, Y. Kimura, K. Inokuchi, T. Tagawa, H. Shimokawa, A. Takeshita, and K. Sunagawa Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure Circulation, May 31, 2005; 111(21): 2741 - 2747. [Abstract] [Full Text] [PDF]
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 R. Rossi, E. Cioni, A. Nuzzo, G. Origliani, and M. G. Modena Endothelial-Dependent Vasodilation and Incidence of Type 2 Diabetes in a Population of Healthy Postmenopausal Women Diabetes Care, March 1, 2005; 28(3): 702 - 707. [Abstract] [Full Text] [PDF]
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T. Djordjevic, R. S. BelAiba, S. Bonello, J. Pfeilschifter, J. Hess, and A. Gorlach Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 519 - 525. [Abstract] [Full Text] [PDF]
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G. Loirand, M. Rolli-Derkinderen, and P. Pacaud RhoA and resistance artery remodeling Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1051 - H1056. [Abstract] [Full Text] [PDF]
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T. Hattori, H. Shimokawa, M. Higashi, J. Hiroki, Y. Mukai, H. Tsutsui, K. Kaibuchi, and A. Takeshita Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice Circulation, May 11, 2004; 109(18): 2234 - 2239. [Abstract] [Full Text] [PDF]
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 H.-C. Chen and E. P. Feener MEK1,2 response element mediates angiotensin II--stimulated plasminogen activator inhibitor-1 promoter activation Blood, April 1, 2004; 103(7): 2636 - 2644. [Abstract] [Full Text] [PDF]
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T. Hattori, H. Shimokawa, M. Higashi, J. Hiroki, Y. Mukai, K. Kaibuchi, and A. Takeshita Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice Circ. Res., January 9, 2004; 94(1): 46 - 52. [Abstract] [Full Text] [PDF]
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Z. Mallat, A. Gojova, V. Sauzeau, V. Brun, J.-S. Silvestre, B. Esposito, R. Merval, H. Groux, G. Loirand, and A. Tedgui Rho-Associated Protein Kinase Contributes to Early Atherosclerotic Lesion Formation in Mice Circ. Res., October 31, 2003; 93(9): 884 - 888. [Abstract] [Full Text] [PDF]
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M. Higashi, H. Shimokawa, T. Hattori, J. Hiroki, Y. Mukai, K. Morikawa, T. Ichiki, S. Takahashi, and A. Takeshita Long-Term Inhibition of Rho-Kinase Suppresses Angiotensin II-Induced Cardiovascular Hypertrophy in Rats In Vivo: Effect on Endothelial NAD(P)H Oxidase System Circ. Res., October 17, 2003; 93(8): 767 - 775. [Abstract] [Full Text] [PDF]
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 A. Konishi and B. C. Berk Epidermal Growth Factor Receptor Transactivation Is Regulated by Glucose in Vascular Smooth Muscle Cells J. Biol. Chem., September 12, 2003; 278(37): 35049 - 35056. [Abstract] [Full Text] [PDF]
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 K. K. Koh, J. Y. Ahn, S. H. Han, D. S. Kim, D. K. Jin, H. S. Kim, M.-S. Shin, T. H. Ahn, I. S. Choi, and E. K. Shin Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients J. Am. Coll. Cardiol., September 3, 2003; 42(5): 905 - 910. [Abstract] [Full Text] [PDF]
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 D. Thumkeo, J. Keel, T. Ishizaki, M. Hirose, K. Nonomura, H. Oshima, M. Oshima, M. M. Taketo, and S. Narumiya Targeted Disruption of the Mouse Rho-Associated Kinase 2 Gene Results in Intrauterine Growth Retardation and Fetal Death Mol. Cell. Biol., July 15, 2003; 23(14): 5043 - 5055. [Abstract] [Full Text] [PDF]
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 A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]
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C. Yan, D. Kim, T. Aizawa, and B. C. Berk Functional Interplay Between Angiotensin II and Nitric Oxide: Cyclic GMP as a Key Mediator Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 26 - 36. [Abstract] [Full Text] [PDF]
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 N. Kobayashi, S. Horinaka, S.-i. Mita, S. Nakano, T. Honda, K. Yoshida, T. Kobayashi, and H. Matsuoka Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts Cardiovasc Res, September 1, 2002; 55(4): 757 - 767. [Abstract] [Full Text] [PDF]
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N. Kobayashi, S. Nakano, S.-i. Mita, T. Kobayashi, T. Honda, Y. Tsubokou, and H. Matsuoka Involvement of Rho-Kinase Pathway for Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Gene Expression and Cardiovascular Remodeling in Hypertensive Rats J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 459 - 466. [Abstract] [Full Text] [PDF]
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T. Kaneko, S. Fujii, A. Matsumoto, D. Goto, N. Ishimori, K. Watano, T. Furumoto, T. Sugawara, B. E. Sobel, and A. Kitabatake Induction of Plasminogen Activator Inhibitor-1 in Endothelial Cells by Basic Fibroblast Growth Factor and Its Modulation by Fibric Acid Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 855 - 860. [Abstract] [Full Text] [PDF]
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 R. Samarakoon and P. J. Higgins MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks J. Cell Sci., January 8, 2002; 115(15): 3093 - 3103. [Abstract] [Full Text] [PDF]
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W. A. Hsueh and R. E. Law PPAR{gamma} and Atherosclerosis: Effects on Cell Growth and Movement Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1891 - 1895. [Abstract] [Full Text] [PDF]
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