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J Biol Chem, Vol. 274, Issue 45, 32382-32386, November 5, 1999
From the We have shown previously that angiotensin II (Ang
II) activates the janus-activated kinase (JAK)/signal transducers and
activators of transcription (STAT) pathway in vascular smooth muscle
cells (VSMCs) and that activation of the JAK/STAT pathway is required for Ang II induction of VSMC proliferation. In the present study, we
examined the effects of hyperglycemia (HG) on Ang II-induced JAK/STAT
signaling events in cultured VSMCs. HG increases Ang II-induced JAK2
tyrosine phosphorylation and promotes a partial tyrosine
phosphorylation of the enzyme under basal conditions. In addition, HG
increases both basal and Ang II-induced complex formation of JAK2 with
the Ang II AT1 receptor. The extent of STAT1 and STAT3
tyrosine and serine phosphorylation are also increased under HG
conditions. Furthermore, the tyrosine phosphorylation and activities of
the SHP-1 and SHP-2 tyrosine phosphatases, enzymes that regulate Ang
II-induced JAK2 tyrosine phosphorylation, are altered by HG. SHP-1,
which is responsible for JAK2 tyrosine dephosphorylation in VSMC, is
completely deactivated in HG, resulting in a prolonged duration of JAK2
phosphorylation under HG conditions. HG also enhances Ang II induction
of VSMC proliferation. Taken together, these data suggest that HG
augments Ang II induction of VSMC proliferation by increasing signal
transduction through the JAK/STAT pathway.
A major pathologic complication of diabetes is atherosclerosis
(1). One of the basic underlying causes of diabetic atherosclerosis appears to be hyperglycemia-induced vascular smooth muscle cell (VSMC)1 proliferation. VSMCs
cultured under hyperglycemic (HG) conditions, for example, proliferate
at a significantly faster rate than those cultured under normal glucose
(NG) conditions (2). HG increases the de novo synthesis of
the protein kinase C-activator, diacylglycerol. Thus, one hypothesized
mechanism by which HG induces VSMC proliferation is through the chronic
activation of one or more isoforms of protein kinase C (3). Other
mechanisms by which HG has been suggested to stimulate VSMC
proliferation are through nonenzymatic modification of macromolecules
to form advanced glycation end products, changes in sorbitol and
myoinositol metabolism, increased oxidant formation, and increased
production of extracellular matrix molecules (1, 4).
VSMC proliferation is also stimulated by a number of growth factors and
hormones including angiotensin II (Ang II) (5-8). Furthermore, Ang II
stimulation of VSMC proliferation is very likely enhanced by HG because
Ang II activation of mitogen-activated protein kinases (MAPKs) is
increased in VSMCs cultured under HG conditions (9), and we have shown
previously that activation of the MAPK pathway is essential to Ang II
induction of VSMC proliferation (7, 8). In addition to the MAPK
pathway, a second pathway involved in Ang II induction of VSMC
proliferation is the janus-activated kinase (JAK)/signal transducers
and activators of transcription (STAT) pathway (8). The JAK/STAT
pathway involves the tyrosine phosphorylation and consequent activation
of JAK tyrosine kinases. Activated JAK kinases phosphorylate latent
transcription factors termed STATs, resulting in STAT homo- and
heterodimerization and translocation of STAT dimers to the nucleus. In
the nucleus, STAT dimers bind to specific response elements in gene
promoters and direct transcription (10). Cross-talk also appears to
exist between the MAPK and the JAK/STAT pathways because serine
phosphorylation of STAT1 and STAT3 by MAPK is required for maximal
transcriptional activity of these factors (11).
We have shown previously that Ang II stimulation of VSMCs results in
the tyrosine phosphorylation of JAK2 and complex formation of JAK2 with
the Ang II AT1 receptor (12). We have also demonstrated that Ang II-induced JAK2 tyrosine phosphorylation is regulated by the
protein-tyrosine phosphatases known as SHP-1 and SHP-2 (13) and that
phosphorylation of JAK2 is accompanied by the tyrosine and/or serine
phosphorylation of STAT1 and STAT3 and translocation of the two
proteins to the nucleus (12, 14, 15). This signaling cascade appears to
be essential to Ang II induction of VSMC proliferation, because
treatment of VSMCs with the JAK2 inhibitor, AG-490, or electroporation
of anti-STAT1 or anti-STAT3-neutralizing antibodies completely blocks
Ang II induction of cell proliferation (8).
The JAK/STAT pathway and HG, thus, both have important roles in
promoting VSMC proliferation. It is not known, however, whether HG
affects JAK/STAT signaling in VSMC. Therefore, in the present study we
examined the effects of HG on various Ang II-induced JAK/STAT signaling
events associated with Ang II stimulation of VSMC proliferation.
Materials--
Anti-JAK2 phosphotyrosine-specific antibody was
purchased from BIOSOURCE International. Anti-STAT1
antibody, anti-STAT3 antibody, anti-STAT1 phosphotyrosine-specific
antibody, and anti-STAT3 phosphotyrosine-specific antibody were
obtained from New England BioLabs. Anti-STAT1 phosphoserine-specific antibody and anti-STAT3 phosphoserine-specific antibody were procured from Upstate Biotechnology. Anti-AT1 receptor antibody,
anti-JAK2 antibody, anti-SHP-1 antibody, and anti-SHP-2 antibody were
purchased from Santa Cruz Biotechnology. Anti-phosphotyrosine antibody
came from Transduction Laboratories. Cell Titer 96 AQueous
nonradioactive cell proliferation assay kit was purchased from Promega.
All other chemicals were purchased from Sigma.
Cell Culture--
VSMCs were cultured from aortas of male Harlan
Sprague-Dawley rats in Dulbecco's modified Eagle's medium containing
10% fetal bovine serum and antibiotics as described previously (16).
VSMC passages 8 to 15 were grown to 70-80% confluence, washed once in
serum-free medium, and incubated for 24 h in either NG (5.5 mM), HG (25.0 mM), or NG (5.5 mM)
plus mannitol (19.5 mM) before treatment with Ang II (100 nM).
Immunoprecipitation and Immunoblotting--
Immunoprecipitation
and immunoblotting were carried out as described previously
(13-15).
Tyrosine Phosphatase Activity Assay--
VSMC lysates (1 mg of
protein) were incubated with 3 µg of anti-SHP-1 or anti-SHP-2
antibody at 4 °C. After 3 h, protein A/G agarose was added, and
incubation was continued for 1 h. Immunoprecipitates were
recovered by centrifugation then washed three times in ice-cold wash
buffer containing 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 0.1% Triton X-100 then three times in
phosphatase buffer containing 50 mM HEPES, pH 7.4, 60 mM NaCl, 60 mM KCl, 0.1 mM
phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, and 10 µg/ml
leupeptin. Phosphatase activity was assayed as described previously
(13, 17) by measuring the rate of formation of p-nitrophenol
from of p-nitrophenyl phosphate. The final
immunoprecipitated pellet was suspended in a total of 100 µl of
phosphatase buffer containing 1 mg/ml bovine serum albumin, 5 mM EDTA, and 10 mM dithiothreitol. The reaction
was initiated by the addition of p-nitrophenyl phosphate (10 mM final concentration) and was allowed to proceed for 30 min at room temperature. The reaction was terminated by the addition of
1 M NaOH, and the absorbance of the sample at 410 nM was determined in a spectrophotometer.
Cell Proliferation Assay--
VSMC proliferation was quantitated
using the Cell Titer 96 AQueous nonradioactive cell
proliferation assay kit (Promega). This assay is based on measuring the
cellular conversion of the colorimetric reagent
3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt into a soluble formazan by dehydrogenase enzymes found only in
metabolically active, proliferating cells. The absorbance of formazan
was measured at 490 nM using a 96-well enzyme-linked immunosorbent assay plate reader.
The JAK/STAT signaling pathway in VSMC plays an essential role in
Ang II induction of cell proliferation (8). VSMC proliferation is also
stimulated by HG (2). Whether HG affects JAK/STAT signaling, however,
has not been previously investigated. To determine whether HG alters
either basal or Ang II-induced tyrosine phosphorylation of JAK2, cells
were incubated for 24 h in serum-free medium containing either NG
(5.5 mM glucose) or HG (25 mM glucose) before
stimulation for 0, 1, 5, 10, and 30 min with Ang II (100 nM). Cells were then lysed, and equal amounts of lysate
from each condition (50 µg of protein) were immunoblotted with a JAK2
phosphotyrosine-specific antibody that recognizes the
tyrosine-phosphorylated, but not the nonphosphorylated, form of JAK2.
As shown in Fig. 1, under euglycemic
conditions, Ang II induced a transient tyrosine phosphorylation of JAK2
(130-kDa band) that was maximal between 1 and 5 min. Under HG
conditions, both the extent and the duration of JAK2 phosphorylation were increased, suggesting that HG increases the magnitude and prolongs
the duration of Ang II-induced JAK2 activation in VSMC. In addition, in
HG, JAK2 was partially phosphorylated even under basal conditions,
suggesting that HG promotes a partial constitutive activation of JAK2
even in the absence of Ang II. Lysates were also immunoblotted with an
anti-JAK2 antibody that recognizes both phosphorylated and
nonphosphorylated forms of JAK2. Equal amounts of JAK2 were detected
for all conditions by the nonphospho-specific antibody, indicating that
the differences detected with the phosphotyrosine-specific antibody
were not due to differences in the amount of total JAK2 protein loaded
in each lane. Similar results were also obtained in experiments in
which JAK2 tyrosine phosphorylation was quantitated by
immunoprecipitation with anti-phosphotyrosine antibody followed by
immunoblotting of immunoprecipitates with anti-JAK2 antibody (data not
shown). In the experiment shown in Fig. 1 and in all others described
in the present study, controls were included to determine whether the
effects of HG might be due to hyperosmolarity. Thus, in addition to the
NG control (5.5 mM glucose), we also included a control of
5.5 mM glucose plus 19.5 mM mannitol. In this
experiment, as well as in all other experiments described hereafter, no
effects of hyperosmolarity (glucose plus mannitol) were seen on any of
the JAK/STAT-signaling events examined.
Ang II-induced JAK2 tyrosine phosphorylation in VSMC is accompanied by
complex formation of JAK2 with the Ang II AT1 receptor (12). Complex formation involves association of JAK2 with a YIPP motif
in the C-terminal intracellular domain 4 of the AT1 receptor, an event that appears to be a prerequisite for JAK2 phosphorylation and, hence, activation (18). To determine whether HG
alters either basal or Ang II-induced complex formation of JAK2 with
the AT1 receptor, VSMC were incubated for 24 h in
serum-free medium containing either NG or HG and then stimulated for 0 or 5 min with Ang II (100 nM). Cells were lysed, and the
AT1 receptor was immunoprecipitated from equal amounts of
lysate (1 mg of protein) from each condition. Immunoprecipitated
proteins were then immunoblotted with an anti-JAK2 antibody to
determine whether the AT1 receptor and JAK2
coimmunoprecipitated as a complex. As shown in Fig.
2, under NG conditions, no
AT1 receptor-JAK2 complex was detected in the absence of
Ang II treatment. A complex between the two proteins was detected,
however, following a 5-min exposure to Ang II. Under HG conditions, the
extent of Ang II-stimulated complex formation was significantly
increased, suggesting again that HG enhances Ang II-induced JAK2
signaling in VSMC. Furthermore, in HG, a significant amount of JAK2 was
associated with the AT1 receptor even under basal
conditions, suggesting that HG may cause a non-Ang II-dependent constitutive activation of JAK2 in
VSMC.
Hyperglycemia Enhances Angiotensin II-induced Janus-activated
Kinase/STAT Signaling in Vascular Smooth Muscle Cells*
§,§,,,¶
**, and**
Vascular Biology Center, ¶ Department
of Pediatrics, and Department of Pharmacology and
Toxicology, Medical College of Georgia,
Augusta, Georgia 30912
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
View larger version (36K):
[in a new window]
Fig. 1.
Effects of high glucose on basal and Ang
II-induced tyrosine phosphorylation of JAK2. VSMCs were incubated
for 24 h in serum-free medium containing either NG ( 
, 5.5 mM) or HG (
, 25 mM) and then treated with
Ang II (100 nM) for the times indicated. Cells were lysed,
and lysates were immunoblotted with phosphotyrosine-specific and
nonphosphospecific anti-JAK2 antibodies. Shown are representative
immunoblots and densitometric analysis of three immunoblots probed with
the phosphotyrosine-specific antibody (mean ± S.E.).
Tyr-P, phosphotyrosine.
View larger version (24K):
[in a new window]
Fig. 2.
Effects of high glucose on basal and Ang
II-induced complex formation of JAK2 with the AT1
receptor. VSMCs were incubated for 24 h in serum-free medium
containing either NG (5.5 mM) or HG (25 mM) and
then treated with Ang II (100 nM) for 0 or 5 min. Cells
were lysed, and the AT1 receptor was immunoprecipitated
from lysates with anti-AT1 receptor antibody.
Immunoprecipitates were immunoblotted with anti-JAK2 antibody. Shown is
a representative immunoblot and densitometric analysis of three
immunoblots (mean ± S.E.).
We have shown previously that STAT1 is tyrosine-phosphorylated and that
STAT3 is both tyrosine- and serine-phosphorylated in VSMCs in response
to Ang II stimulation (12, 14, 15). To determine whether HG alters
either the basal or the Ang II-induced tyrosine or serine
phosphorylation of STAT1 or STAT3, we carried out immunoblotting
experiments with phosphospecific antibodies that recognize either the
tyrosine- or the serine-phosphorylated, but not the nonphosphorylated,
forms of STAT1 and STAT3. VSMCs were incubated for 24 h in
serum-free medium containing either NG or HG and then stimulated with
Ang II (100 nM) for 0, 1, 5, 10, 30, or 60 min. Cells were
lysed, and equal amounts of lysate (50 µg of protein) were
immunoblotted with the phosphospecific antibodies. As shown in Fig.
3, both the extent and the duration of
the Ang II-induced tyrosine phosphorylation of STAT1 (92-kDa band,
which is sometimes resolved into a doublet on immunoblots (12)) was
increased in HG. Lysates were also immunoblotted with an anti-STAT1
antibody that recognizes both phosphorylated and nonphosphorylated
forms of STAT1. Equivalent amounts of STAT1 were detected for all time
points by the nonphospho-specific antibody, demonstrating that the
differences detected with the phosphotyrosine-specific antibody were
not due to differences in the amounts of total STAT1 protein. It has
not been previously determined whether Ang II induces serine
phosphorylation of STAT1 in VSMC. Quantitation of serine
phosphorylation of STAT1 in the present study, however, showed that Ang
II does indeed induce the serine phosphorylation of STAT1 in VSMC and
that the level of phosphorylated serine in STAT1 was increased by HG
both in response to Ang II and in the basal state (Fig.
4). When lysates were probed with the
antibody that recognizes both phosphorylated and nonphosphorylated
forms of STAT1, equal amounts of STAT1 protein were detected by the nonphospho-specific antibody in all conditions, indicating that the
differences observed in STAT1 serine phosphorylation were not due to
differences in the amounts of STAT1 protein.
|
|
We next examined the phosphorylation of STAT3. HG increased the extent
of Ang II-induced tyrosine phosphorylation of the protein (89-kDa band,
which is sometimes resolved into a doublet on immunoblots (12)) (Fig.
5) and increased both the extent and the
duration of Ang II-induced serine phosphorylation (Fig.
6). HG also induced serine
phosphorylation of STAT3 under basal conditions. Differences that were
detected in the tyrosine and serine phosphorylation of STAT3 were not
due to differences in the amounts of STAT3 protein as confirmed by
immunoblotting with an anti-STAT3 antibody that recognizes both
phosphorylated and nonphosphorylated forms of STAT3. The results of
these studies of tyrosine and serine phosphorylation of STAT1 and STAT3
demonstrate that HG not only enhances basal and Ang II-induced
JAK/STAT signaling at the level of JAK2 phosphorylation and activation
but also at the level of STAT1 and STAT3 phosphorylation and
activation. We have shown previously that Ang II-induced serine phosphorylation of STAT3 is mediated by MAPK (15). To determine whether
Ang II-induced serine phosphorylation of STAT1 is also mediated by
MAPK, we investigated Ang II-induced serine phosphorylation of the
factor following exposure of VSMC to the MAP kinase kinase (and hence
MAPK) inhibitor, PD98059 (19). Preincubation of cells with the
inhibitor (30 µM for 1 h) completely blocked Ang
II-induced serine phosphorylation of STAT1 (data not shown), confirming
that phosphorylation was catalyzed by MAPK.
|
|
In a previous study, we showed that the cytosolic SH-2
domain-containing protein-tyrosine phosphatases SHP-1 and SHP-2 have important and opposite roles in Ang II-induced JAK2 tyrosine
phosphorylation in VSMC (13). SHP-1 appears to be responsible for JAK2
dephosphorylation and undergoes tyrosine dephosphorylation itself (and
consequently deactivation) during the time period when JAK2 is
maximally phosphorylated. The protein-tyrosine phosphatase is
subsequently tyrosine-phosphorylated and activated during the period of
time when JAK2 is dephosphorylated. The time course of Ang II-induced
SHP-2 tyrosine phosphorylation and activation, on the other hand, is
very different. Phosphorylation and activation of SHP-2 is maximal
during the period of time when JAK2 tyrosine phosphorylation is
maximal. Furthermore, as we have also reported previously, SHP-2
functions as an adaptor protein for JAK2 association with the
AT1 receptor (13). Because this association is required for
JAK2 tyrosine phosphorylation (18), SHP-2, in its role as an adaptor,
facilitates Ang II-induced JAK2 tyrosine phosphorylation. To determine
whether HG affects the Ang II-induced tyrosine phosphorylation and
activity of SHP-2 in VSMC, cells were incubated for 24 h in
serum-free medium containing either NG or HG and then stimulated with
Ang II (100 nM) for 0, 1, 5, 10, or 30 min. Cells were
lysed, and equal amounts of lysate (1 mg of protein) were
immunoprecipitated with anti-SHP-2 antibody. Immunoprecipitated
proteins were immunoblotted with anti-phosphotyrosine antibody. As
shown in Fig. 7A, in NG, Ang
II induced a tyrosine phosphorylation of SHP-2 that was maximal at 5 to
10 min and was partially sustained for at least 30 min. In HG, the time
course of Ang II-induced tyrosine phosphorylation of SHP-2 was similar to that in NG except that the extent of phosphorylation was
approximately 2-fold higher at each time point.
Immunoprecipitated SHP-2 proteins in these experiments were also
assayed for tyrosine dephosphorylation activity by monitoring the rate
of formation of p-nitrophenol from p-nitrophenyl
phosphate as described previously (13, 17). As shown in Fig.
7B, SHP-2 activities for each time point and for each
condition were altered in parallel with changes in SHP-2 tyrosine
phosphorylation with approximately 2-fold higher activities in HG as
compared with NG. HG thus appears to enhance the effects of Ang II on
both SHP-2 tyrosine phosphorylation and SHP-2 activity.
|
To determine whether HG influences the Ang II-induced tyrosine
phosphorylation and activity of SHP-1 in VSMC, cells were incubated for
24 h under either NG or HG conditions before stimulation with Ang
II (100 nM) for 0, 1, 5, 10, or 30 min. Cells were lysed, and SHP-1 was immunoprecipitated from lysates (1 mg of lysate protein
from each condition) with anti-SHP-1 antibody. SHP-1 tyrosine phosphorylation and activity were then quantitated as described above
for SHP-2. In NG, SHP-1 was transiently dephosphorylated in response to
Ang II followed by a subsequent rephosphorylation to a level greater
than that under basal conditions (Fig.
8A). SHP-1 catalytic activity
in NG was also reduced in parallel followed by a subsequent increase
(Fig. 8B). In HG, SHP-1 was completely dephosphorylated and
completely devoid of catalytic activity both under basal conditions as
well as after Ang II stimulation (Figs. 8, A and
B). HG thus appears to cause a complete deactivation of
SHP-1 in VSMC. Because SHP-1 is responsible for JAK2 dephosphorylation in VSMC (13), these results provide an explanation for the increased JAK2 phosphorylation observed under HG conditions (Fig. 2). Increased JAK2 tyrosine phosphorylation in HG both basally and in response to Ang
II is likely due to a lack of SHP-1 activity in HG and, hence, a lack
of dephosphorylation of JAK2.
|
Both hyperglycemia and Ang II are capable of stimulating VSMC
proliferation (2, 7, 8). Furthermore, Ang II stimulation of VSMC
proliferation may be augmented by HG. This hypothesis follows from the
observation of Natarajan et al. (9) that Ang II activation
of MAPKs in VSMCs is enhanced in HG. We have shown previously that MAPK
activation is important in Ang II induction of cell proliferation (7,
8). Whether HG augments Ang II induction of VSMC proliferation,
however, has not been previously demonstrated. To determine whether HG
enhances the Ang II induction of VSMC proliferation, cells were
cultured in NG, NG plus Ang II (100 nM), or HG plus Ang II
(100 nM). Cell proliferation was then quantitated over a
period of 48 h by a colorimetric assay that determines the level
of activity of dehydrogenase enzymes found only in metabolically
active, proliferating cells. As shown in Fig.
9, HG does indeed enhance Ang II
induction of VSMC proliferation with the effect of Ang II in
stimulating cell proliferation being approximately 2-fold higher in HG
relative to that in NG.
|
In summary, the results of the present study demonstrate that HG has
significant effects on multiple basal and Ang II-induced JAK/STAT
signaling events in VSMC as well as on Ang II induction of VSMC
proliferation. Thus, in addition to the previously known effects of HG
on chronic activation of protein kinase C isoforms and on basal and Ang
II-induced activation of MAPK isozymes, HG appears to also augment Ang
II induction of VSMC proliferation by increasing signal transduction
through the JAK/STAT pathway.
| |
ACKNOWLEDGEMENT |
|---|
We thank Sandra M. Jean-Pierre for preparation of the manuscript.
| |
FOOTNOTES |
|---|
* This work was supported by National Institutes of Health Grants HL57201, HL58139, and HL62152, an American Heart Association grant-in-aid award, and an American Heart Association/Astra-Merck grant-in-aid award.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ These authors contributed equally to this work.
** To whom correspondence should be addressed: Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500. Tel.: 706-721-2576; Fax: 706-721-8555; E-mail: rvenema@mail.mcg.edu (for R. C. V) or mmarrero@mail.mcg.edu (for M. B. M).
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ABBREVIATIONS |
|---|
The abbreviations used are: VSMC, vascular smooth muscle cell; HG, high glucose or hyperglycemic; NG, normal glucose; Ang II, angiotensin II; JAK, janus-activated kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; SHP, SH2 domain-containing protein phosphatase.
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TOP
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RESULTS AND DISCUSSION
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N.-H. Kim, H. Rincon-Choles, B. Bhandari, G. G. Choudhury, H. E. Abboud, and Y. Gorin Redox dependence of glomerular epithelial cell hypertrophy in response to glucose Am J Physiol Renal Physiol, March 1, 2006; 290(3): F741 - F751. [Abstract] [Full Text] [PDF]
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 X. C. Li, O. A. Carretero, Y. Shao, and J. L. Zhuo Glucagon Receptor-Mediated Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells: Role of Protein Kinase A and Phospholipase C Hypertension, March 1, 2006; 47(3): 580 - 585. [Abstract] [Full Text] [PDF]
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 V. Portik-Dobos, A. K. Harris, W. Song, J. Hutchinson, M. H. Johnson, J. D. Imig, D. M. Pollock, and A. Ergul Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2006; 290(2): R435 - R441. [Abstract] [Full Text] [PDF]
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 S. Sahar, R. S. Dwarakanath, M. A. Reddy, L. Lanting, I. Todorov, and R. Natarajan Angiotensin II Enhances Interleukin-18 Mediated Inflammatory Gene Expression in Vascular Smooth Muscle Cells: A Novel Cross-Talk in the Pathogenesis of Atherosclerosis Circ. Res., May 27, 2005; 96(10): 1064 - 1071. [Abstract] [Full Text] [PDF]
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 N. R. Madamanchi, S.-K. Moon, Z. S. Hakim, S. Clark, A. Mehrizi, C. Patterson, and M. S. Runge Differential Activation of Mitogenic Signaling Pathways in Aortic Smooth Muscle Cells Deficient in Superoxide Dismutase Isoforms Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 950 - 956. [Abstract] [Full Text] [PDF]
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 I. Guillet-Deniau, A.-L. Pichard, A. Kone, C. Esnous, M. Nieruchalski, J. Girard, and C. Prip-Buus Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway J. Cell Sci., April 15, 2004; 117(10): 1937 - 1944. [Abstract] [Full Text] [PDF]
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A. K. Banes, S. Shaw, J. Jenkins, H. Redd, F. Amiri, D. M. Pollock, and M. B. Marrero Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli Am J Physiol Renal Physiol, April 1, 2004; 286(4): F653 - F659. [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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 S. S. Shaw, A. M. Schmidt, A. K. Banes, X. Wang, D. M. Stern, and M. B. Marrero S100B-RAGE-Mediated Augmentation of Angiotensin II-Induced Activation of JAK2 in Vascular Smooth Muscle Cells Is Dependent on PLD2 Diabetes, September 1, 2003; 52(9): 2381 - 2388. [Abstract] [Full Text] [PDF]
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S. Shaw, X. Wang, H. Redd, G. D. Alexander, C. M. Isales, and M. B. Marrero High Glucose Augments the Angiotensin II-induced Activation of JAK2 in Vascular Smooth Muscle Cells via the Polyol Pathway J. Biol. Chem., August 15, 2003; 278(33): 30634 - 30641. [Abstract] [Full Text] [PDF]
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M. Hortala, G. Ferjoux, A. Estival, C. Bertrand, S. Schulz, L. Pradayrol, C. Susini, and F. Clemente Inhibitory Role of the Somatostatin Receptor SST2 on the Intracrine-regulated Cell Proliferation Induced by the 210-Amino Acid Fibroblast Growth Factor-2 Isoform: IMPLICATION OF JAK2 J. Biol. Chem., May 30, 2003; 278(23): 20574 - 20581. [Abstract] [Full Text] [PDF]
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 C. P. Sodhi, Y. S. Kanwar, and A. Sahai Hypoxia and high glucose upregulate AT1 receptor expression and potentiate ANG II-induced proliferation in VSM cells Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H846 - H852. [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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X. Wang, S. Shaw, F. Amiri, D. C. Eaton, and M. B. Marrero Inhibition of the JAK/STAT Signaling Pathway Prevents the High Glucose-Induced Increase in TGF-{beta} and Fibronectin Synthesis in Mesangial Cells Diabetes, December 1, 2002; 51(12): 3505 - 3509. [Abstract] [Full Text] [PDF]
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G. D. Frank, S. Saito, E. D. Motley, T. Sasaki, M. Ohba, T. Kuroki, T. Inagami, and S. Eguchi Requirement of Ca2+ and PKC{delta} for Janus Kinase 2 Activation by Angiotensin II: Involvement of PYK2 Mol. Endocrinol., February 1, 2002; 16(2): 367 - 377. [Abstract] [Full Text] [PDF]
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