(Hypertension. 1997;30:106-111.)
© 1997 American Heart Association, Inc.
Articles |
Induction of Mitogen-Activated Protein Kinase Phosphatase-1 During Acute Hypertension
From the Gene Expression and Aging Section, National Institute on Aging, National Institutes of Health, Baltimore, Md.
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Abstract |
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Abstract Recently, we demonstrated that elevated blood pressure activates mitogen-activated protein (MAP) kinases in rat aorta. Here we provide evidence that the vascular response to acute hypertension also includes induction of MAP kinase phosphatase-1 (MKP-1), which has been shown to function in the dephosphorylation and inactivation of MAP kinases. Restraint or immobilization stress, which leads to a rapid rise in blood pressure, resulted in a rapid and transient induction of MKP-1 mRNA followed by elevated MKP-1 protein expression in rat aorta. That the induction of MKP-1 by restraint was due to the rise in blood pressure was supported by the finding that several different hypertensive agents (phenylephrine, vasopressin, and angiotensin II) were likewise capable of eliciting the response, and sodium nitroprusside, a nonspecific vasodilator agent that prevented the acute rise in blood pressure in response to the hypertensive agents, abrogated MKP-1 mRNA induction. The in vivo effects could not be mimicked by treatment of cultured aortic smooth muscle cells with similar doses of the hypertensive agents. These findings support a role for MKP-1 in the in vivo regulation of MAP kinase activity during hemodynamic stress.
Key Words: phosphoprotein phosphatase • protein kinases • stress • cardiovascular system
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Intracellular signaling following stimulation by growth factors, cytokines, and stresses involves the initiation of one or more phosphorylation cascades leading to the rapid and reversible activation of MAP kinases, a ubiquitous group of serine/threonine kinases thought to play a pivotal role in regulating cellular events required for cell growth, differentiation, and homeostasis.1 2 3 4 5 JNK (also referred to as stress-activated protein kinases) and ERK constitute two distinct subfamilies of MAP kinases that are responsible for the activation and phosphorylation of a variety of other regulatory proteins, including transcription factors involved in regulating gene expression.5 6 7 8 9
The activities of ERK and JNK are regulated by reversible phosphorylation of tyrosine and threonine residues, and several protein phosphatases with high specificity for MAP kinases have been described. These include MKP-1 (its human homologue is referred to as CL100 or 3CH134), MKP-2, MKP-3, PAC-1, and B23.10 11 12 13 14 15 16 17 18 MKP-1, the most ubiquitously expressed and best studied of these phosphatases, is capable of dephosphorylating phosphothreonine and phosphotyrosine residues of ERK, JNK, and a third subfamily of MAP kinases, p38, although it shows greatest selectivity for ERK.11 12 19 20 MKP-1 has been implicated in a feedback loop serving to regulate MAP kinase activity in response to mitogenic stimulation as well as during the cellular response to stress.11 12 13 19 21 However, little is known about MKP-1 gene expression in vivo—its physiological role or relevance to pathological conditions in either animals or humans.
A number of in vitro studies have suggested the involvement of MAP kinase signaling pathways in the regulation of gene expression in cardiovascular tissues, particularly those believed to participate in the hypertrophic adaptive response to stress.22 23 24 25 26 27 28 We have recently demonstrated that ERK and JNK MAP kinases are activated in vivo in the arterial wall of rats subjected to conditions resulting in acute hypertension.29 In the present study, we examined the relationship between blood pressure and MKP-1 expression in the vasculature. We demonstrate that acute hypertension elicited by either restraint or hypertensive agents leads to the rapid induction of MKP-1 expression in rat aorta and further characterize the response.
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Methods |
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Animals and Restraint Model
Four-month-old male Wistar rats were obtained from Hilltop Lab Animals, Inc (Scottdale, Pa) and acclimated in individual cages for 1 week before experimentation. Rats were maintained on a 12-hour light/dark cycle at 24°C and received food and water ad libitum. All procedures were performed according to protocols approved by the National Institute on Aging Committee for use and care of laboratory animals in accordance with guidelines established by the National Institutes of Health. For restraint experiments, individual animals were placed in clear ventilated Plexiglas chambers as described previously.30
Blood Pressure Measurements
Rats underwent light anesthesia with thiopental (40
mg/kg IM) followed by insertion of polyethylene catheters via the
common femoral artery and vein into the abdominal aorta and
inferior vena cava, respectively.31 32 The
aortic catheter was connected to a pressure transducer (COBE) and blood
pressure analyzer (Micro-MED Inc). A bolus injection of various
agents or saline was administered via the vena caval catheter, and
blood pressure measurements were made every 30 seconds up to 30
minutes. The doses of the pharmacological agents were calculated
on a microgram-per-kilogram basis as determined by their ability to
produce consistent hypertensive responses without demonstrable
side effects.31
Chronic Catheterization Procedure and Drug
Administration
Polyethylene catheters were inserted via the common femoral vein
into the inferior vena cava with rats under thiopental (40
mg/kg IM) anesthesia.31 32 The catheters were
tunneled through the subcutaneous tissue to exit from the back where
they were connected to a swivel device (Rodent Multi-fluid Channel
Swivel, Stoelting Co). This model allows for complete animal mobility
so that subsequent experiments could be performed in conscious,
unstressed animals. Saline (0.4 mL) was injected through the catheter
daily for 3 days after its insertion. Phenylephrine (140
µg/kg), Ang II (2 µg/kg), vasopressin (2 µg/kg), and sodium
nitroprusside (1 mg/kg) (Sigma Chemical Co) were administered via the
catheter into the vena cava.
Cell Culture
Vascular smooth muscle cells were isolated from rats by
enzymatic digestion of the aorta according to the procedure of Ross and
Kariya33 and were cultured in medium 199 (GIBCO)
supplemented with 20% fetal calf serum, penicillin (100 U/mL), and
streptomycin (100 µg/mL). Cells were incubated at 37°C in a
humidified atmosphere of 5% CO2 in air. The medium was
changed every 3 days, and cells were passaged by treatment with 0.05%
trypsin/0.02% EDTA. Experiments were conducted on early-passage cells
(passages 3 through 5) that had just achieved confluence. Rat serum or
various drugs prepared fresh before use were added to the cultures.
After incubation at 37°C for the indicated times, cells were
harvested for RNA analysis.
RNA Extraction and Northern Analysis
Freshly harvested tissues or cells were homogenized
and the RNA extracted with RNA Stat-60 (Tel-Test "B" Inc). Total
RNA (10 µg per lane) was fractionated by electrophoresis on
formaldehyde-agarose gels and transferred to nylon membranes
(GeneScreen Plus, DuPont). Hybridizations were performed with an
-32P–labeled cDNA probe for MKP-119 as
previously described.32 Differences in loading and
transfer were assessed by quantitative analysis of 18S levels
on the same blots. Autoradiographs of the blots were obtained in
the linear range of detection and were quantified for levels of
specific expression by scanning laser densitometry (Molecular
Dynamics).
Western Analysis and ERK2 Assays
Aortic tissue was homogenized with a Polytron
homogenizer (PT1200, Kinematica AG) at setting No. 6
for 30 seconds on ice in a buffer containing 20 mmol/L HEPES (pH
7.5), 1.5 mmol/L MgCl2, 0.2 mmol/L EDTA, 0.4
mol/L NaCl, 0.2 mmol/L dithiothreitol, 1 mmol/L Pefablock SC
(Boehringer Mannheim), 20% glycerol, and 1 µg/mL leupeptin.
The homogenate was incubated on ice for 15 minutes and
centrifuged at 17 000g for 30 minutes. The
supernatant was harvested and protein concentration measured with a
protein assay reagent (Bio-Rad). Western analysis was performed
as described previously using an antibody specific to MKP-1 (Santa Cruz
Biotechnology).
ERK2 protein was immunoprecipitated from tissue with anti-p42ERK2 antiserum (Santa Cruz Biotechnology) and its activity assayed as described previously29 using myelin basic protein (Sigma) as a substrate.
Statistical Analysis
An unpaired Student's t test was used to assess
differences between two groups. A value of P<.05 was
considered significant.
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Results |
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MKP-1 Expression in Response to Restraint and Hypertensive Agents
We have shown previously that restraint, a moderate behavioral stress, results in a rapid elevation in systemic blood pressure and transient activation (maximal effect seen at 10 minutes) of MAP kinases, including ERK and JNK.29 To determine a possible relationship between blood pressure elevation and aortic MKP-1 expression, we measured arterial blood pressure and analyzed aortic MKP-1 mRNA after restraint stress. In keeping with our previous studies, restraint resulted in a rapid rise (within 2 minutes) in systemic blood pressure (systolic, from 120 to 150-160 mm Hg), which was maintained for the entire 60-minute period of restraint (Fig 1A
). The effect of restraint stress on MKP-1
mRNA levels is shown in Fig 1B and 1C. Restraint resulted in the rapid
induction of MKP-1, with maximal levels (>20-fold elevation
over those of untreated controls) achieved within 30 minutes of
restraint. Despite the fact that the blood pressure remained elevated,
the MKP-1 mRNA level declined with longer periods of
restraint. This effect appears to be relatively selective for
MKP-1 as attempts to hybridize the same or duplicate blots
with probes to several other members of this phosphatase family (ie,
MKP-2, PAC1, and B23) showed little if
any expression of any of these MKP mRNAs (data not
shown).
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We used Western analysis to examine MKP-1 protein expression in
vessels of rats subjected to restraint (Fig 2). MKP-1
protein was expressed in the aortic tissue even in the absence of
stress, but in keeping with the induction of MKP-1 mRNA,
MKP-1 protein levels were elevated more than twofold within 30 minutes
after restraint. However, more extensive kinetic analysis
indicated that in contrast to the transient nature of the mRNA
response, MKP-1 protein levels remained elevated for at least up to 5
hours after restraint (Fig 2B).
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To further explore the relationship between blood pressure and
MKP-1 expression, we examined the effect of the various
hypertensive agents on MKP-1 mRNA induction.
Phenylephrine, Ang II, and vasopressin, all of which
produce an acute, transient (lasting less than 5 minutes) elevation in
systemic blood pressure associated with activation of ERK and JNK (see
Reference 2929 ), led to an elevation in MKP-1 mRNA levels (Fig 3). The ability of these agents to induce
MKP-1 expression was highly specific to the vasculature, as
other tissues, including kidney, liver, spleen, adrenal glands, and
testis, showed no alteration in MKP-1 mRNA levels in
response to the hypertensive agents (data not shown).
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Antihypertensive Agents Block MKP-1 Expression
The hypertensive agents tested above mediate their effects on
blood pressure via interaction with distinct receptors on the surface
of vascular smooth muscle cells. Therefore, it was of interest to
determine whether MKP-1 expression induced by any of these
agents could be prevented by use of a nonspecific vasodilator agent.
Accordingly, sodium nitroprusside was administered before injection of
the hypertensive agents. We have previously shown that sodium
nitroprusside completely blocks the elevation in blood pressure and
associated MAP kinase activation by restraint as well as hypertensive
agents.29 Likewise, measurement of MKP-1 mRNA
levels revealed that sodium nitroprusside uniformly prevented
MKP-1 induction in response to these treatments (Fig 4). These experiments indicate that the induction of
vascular MKP-1 expression by restraint and the other
agents tested depended on an elevation of blood pressure.
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We obtained further support for this notion from studies examining the
effects of these agents on MKP-1 expression in aortic smooth
muscle cells derived from primary cultures. We reasoned that if
MKP-1 expression were mediated via receptor interactions
independent of the effects of these agents on blood pressure, we would
expect to observe MKP-1 induction after treatment with at
least some of these agents in vitro. On the other hand, if induction
occurred secondary to the elevation in blood pressure caused by these
agents, no increase in MKP-1 expression would occur in
cultured cells. In the experiment shown in Fig 5A, cells
were treated in the presence of 20% fetal calf serum. As shown, no
increase in MKP-1 expression was observed in the smooth
muscle cell cultures treated with any of the hypertensive agents
tested. In this experiment, we also investigated the possibility that
serum from restrained animals contains a factor responsible for
MKP-1 induction. In keeping with previous studies indicating
that MKP-1 expression is elevated in response to
serum,11 13 a modest increase in MKP-1 mRNA
levels was observed in cultures treated with 20% rat serum (relative
to saline-treated controls). However, the MKP-1 mRNA levels
were similar in cells treated with serum both from unrestrained and
restrained animals.
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As the preceding experiment was performed with cells maintained
in the presence of 20% fetal calf serum, we sought to determine
whether the presence of serum and/or the growth state of the cells
influenced their responsiveness to the vasoactive agents. Therefore, we
performed a similar experiment in cells that had been serum-starved for
24 hours before treatment with the hypertensive agents or readdition of
serum (Fig 5B
). No significant induction was observed with any of the
agents at the doses tested, except serum, which as expected, caused a
substantial increase in MKP-1 expression.
Ang II has been shown to induce MKP-1 expression in cultured
smooth muscle cells, albeit at higher doses than those used
above.24 34 To verify that the cultured smooth muscles
cells were indeed capable of responding to higher doses of Ang II, we
performed an additional experiment in which we examined the effects of
various doses of the agent on MKP-1 expression. As shown in
Fig 5C, high Ang II concentrations do lead to MKP-1
induction in the cultured cells. However, taken together, the lack of
MKP-1 induction in cultured cells at doses capable of
eliciting the response in vivo and the ability of sodium nitroprusside
to prevent induction by hypertensive agents in the intact animal argue
strongly that MKP-1 induction in vivo occurs as a response
to an elevation in systemic blood pressure.
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Discussion |
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The growth and proliferation of smooth muscle cells is associated with a number of vascular disease states, including medial hypertrophy in hypertension,35 36 intimal thickening in atherosclerosis,37 38 and restenosis after angioplasty.39 Multiple factors, including growth factors, cytokines, mechanical stress, neurotransmitters, and hormones, are believed to contribute to the processes leading to the hypertrophic response. Recent studies have provided evidence that MAP kinases play a role in regulating key events leading to the adaptive response by mediating the acute alterations in gene expression that occur in response to a variety of stressful stimuli.22 Although most studies have been performed with either cultured cells or severe conditions of stress in vivo, we have shown previously that an acute, modest elevation in blood pressure achieved with restraint or immobilization stress is capable of activating both ERK and JNK in rat aorta.29 These findings emphasize the importance of MAP kinase–dependent gene expression in the cardiovascular system under physiologically relevant conditions of stress. In the present study, we have demonstrated that these same conditions also lead to enhanced expression of MKP-1, a phosphatase believed to play a critical role in regulating MAP kinase activity. Although there is substantial evidence to support a role for MKP-1 in regulating MAP kinase–dependent processes during the cellular response to proliferative and stressful stimuli in cultured cells,12 13 19 21 23 34 little is known concerning its expression and function in vivo. Our studies provide evidence supporting a role for this phosphatase in regulating MAP kinase activity during the host response to hemodynamic stress.
Although the precise signal transduction pathways and transcription factors responsible for MKP-1 expression remain to be clarified, MKP-1 induction does appear to be largely dependent on MAP kinase activation.11 13 19 21 34 Thus, we propose that MKP-1 functions in a feedback loop to regulate MAP kinase activity during the hypertensive response in vivo. Importantly, however, the kinetics of MAP kinase activation and MKP-1 expression with restraint are such that both ERK and JNK are largely inactivated before significant induction of MKP-1 protein; MAP kinase activity peaks within 10 minutes of restraint, with a return to near baseline levels by 30 minutes of restraint.29 Therefore, either basal MKP-1 protein levels are sufficient to accomplish the inactivation or some other phosphatase is responsible for this effect. However, the sustained elevation in MKP-1 protein (evident for up to at least 5 hours after restraint) that occurs in response to the acute hypertensive episode could be important for preventing further MAP kinase activation in response to a subsequent hypertensive episode or during chronic stress. We have obtained preliminary support for this notion in an experiment in which prior restraint (resulting in elevated levels of MKP-1 protein) was associated with reduced activation of ERK in vessels of rats subjected to a second period of restraint 60 minutes later.
Our findings in vivo are in keeping with observations of Duff et al23 and Lai et al,40 who provided evidence that MKP-1 could regulate ERK activity in cultured vascular smooth muscle cells treated with Ang II and serum stimulation, respectively. In addition, Lai et al recently observed an inverse correlation between p44 MAP kinase activity and MKP-1 expression in rat carotid artery after balloon injury. It is likely that the balance between MKP-1 (as well as related phosphatases) and MAP kinase levels/activities in vascular smooth muscle tissue is important for maintaining homeostasis of the arterial wall. Further understanding of the mechanisms regulating MAP kinase and MAP kinase phosphatase activities could lead to strategies aimed at the prevention or treatment of vascular disorders.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to Dr Nikki J. Holbrook, Gene Expression and Aging Section, National Institute on Aging, National Institutes of Health, 4940 Eastern Ave, Baltimore, MD 21224.
Received August 5, 1996; first decision August 27, 1996; accepted December 17, 1996.
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