© 2000 American Heart Association, Inc.
Thrombosis |
Role of the Angiotensin AT1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression
From the Research Division, Joslin Diabetes Center (H.-C.C., J.L.B., A.C.C., E.P.F.), and Beth Israel Deaconess Medical Center (A.S.P., S.I., J.H.), Harvard Medical School, Boston, Mass.
Correspondence to Edward P. Feener, PhD, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail Edward.Feener{at}joslin.harvard.edu
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Abstract |
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Abstract—Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT1) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT1 antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg2-Phe8 (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT1 antagonist candesartan. Angiotensin Val3-Phe8 (Ang IV) and angiotensin Asp1-Pro7 (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (P<0.01), and this response was completely blocked by AT1 receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17- and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (P<0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (P<0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT1 receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression.
Key Words: angiotensin II • plasminogen activator inhibitor • hypertension • aorta • vascular smooth muscle cells
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Introduction |
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Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of tissue and urokinase plasminogen activators and thereby reduces the conversion of plasminogen to plasmin, an extracellular protease that mediates fibrinolysis and activates matrix metalloproteinases.1 2 3 An elevated level of PAI-1, which occurs in diabetes, insulin resistance, obesity, and hypertension, has been implicated as a contributing risk factor for cardiovascular disease.4 5 6 7 Recent studies suggest that the renin-angiotensin system (RAS) may exert an important role in the regulation of circulating and vascular PAI-1 expression and may thereby affect the fibrinolytic balance. Reports from our laboratory and others have demonstrated that angiotensin II (Ang II) is a potent stimulator of PAI-1 mRNA and protein expression in both cultured endothelial and vascular smooth muscle cells.8 9 10 11 The physiological importance of the RAS in modulating PAI-1 levels is supported by in vivo studies, which have demonstrated that treatment of rats with the angiotensin-converting enzyme (ACE) inhibitor captopril suppresses the induction of PAI-1 expression in the aortic neointima induced by balloon catheter injury,12 and a number of clinical studies, which have shown that the ACE inhibitors and the angiotensin type 1 (AT1) receptor antagonist reduce plasma PAI-1 antigen and activity.7 13 14 15 16 17 Although these reports provide substantial evidence for an important role of the RAS in PAI-1 expression, the specific effects of angiotensin-related peptides and the role of the AT1 receptor in regulating PAI-1 expression remain controversial.
The RAS involves the proteolytic conversion of angiotensinogen to Ang I by renin, followed by its conversion to the octapeptide Ang II (Asp1-Phe8) by either ACE or chymase.18 19 Ang II activates 2 receptor subtypes, including AT1 and AT2.20 21 In addition, Ang I and Ang II can undergo further processing to generate other biologically active peptides, including angiotensin Arg2-Phe8 (Ang III), angiotensin Val3-Phe8 (Ang IV), and angiotensin Asp1-Pro7 (Ang [1-7]), which may partially activate AT1 and AT2 or bind additional vascular receptors.21 22 23 Previous studies have shown that the AT1 antagonist losartan partially blocks Ang II–induced PAI-1 expression in rat aortic smooth muscle cells (RASMCs) and rat microvessel endothelial cells.9 In contrast, other reports have suggested that the AT1 receptor does not mediate Ang II–stimulated PAI-1 expression.24 25 Establishing the role of the AT1 receptor in the regulation of PAI-1 expression may have important clinical significance related to potential differences between ACE inhibitors and AT1 antagonists on the fibrinolytic system.
In this report, the effects of angiotensin peptides and the role of the AT1 receptor on PAI-1 mRNA expression in RASMCs and in rat cardiomyocytes were evaluated by using candesartan, previously described as an insurmountable AT1 antagonist.26 The in vivo role of the AT1 receptors in aortic and cardiac PAI-1 expression was evaluated in rats subjected to short-term intrajugular Ang II infusion and in spontaneously hypertensive rats (SHRs) chronically treated with candesartan. These in vitro and in vivo studies demonstrate that the AT1 receptor influences vascular PAI-1 gene expression.
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Methods |
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Cell Culture
RASMCs were isolated from Sprague-Dawley rats, cultured in Dulbecco’s modified Eagle’s medium (DMEM), 100 mg/dL D-glucose (Gibco-BRL), and 10% fetal bovine serum (Gibco-BRL), as described previously,9 and used between passages 8 and 15. Confluent monolayers of cells were deprived of serum in DMEM containing 0.1% (wt/vol) bovine serum albumin for 18 hours before stimulation. Neonatal rat cardiac myocyte primary cultures were prepared as described previously.27 A total of 8x106 cells were plated onto 100-mm gelatin-coated culture dishes in supplemented DMEM/F12 medium27 containing 5% horse serum and 100 µmol/L bromodeoxyuridine. After the first 24 hours, cultures were serum-deprived for 48 hours in DMEM/F12 containing 0.1% bovine serum albumin. Cells were stimulated with angiotensin peptides (Sigma) in the absence or presence of pretreatment with candesartan (CV 11974), kindly provided by Dr Peter Morsing (Astra Hassle AB, Mölndal, Sweden).
RNA Isolation and Northern Blot Analysis
Total RNA was isolated by using Tri reagent (Molecular Research
Center). RNA was separated by agarose gel electrophoresis, and PAI-1
mRNA was probed with a cDNA probe against rat PAI-1, as described
previously.9 Expression of acidic ribosomal phosphoprotein
(36B4) RNA levels was determined by Northern analysis with a
32P-labeled oligonucleotide
probe. Levels of mRNA were visualized and quantified by PhosphorImager
analysis (Molecular Dynamics Inc).
Intrajugular Infusion
A catheter was securely inserted into the left jugular vein of
male Sprague-Dawley rats, and the animals were allowed to recover for
at least 18 hours. Awake rats were then connected to a multisyringe
pump to provide an intravascular infusion of saline alone (control) or
saline containing Ang II and/or candesartan. The infusion rates were
100 ng · kg-1 ·
min-1 Ang II and 25 µg ·
kg-1 · min-1
candesartan (a 50-fold molar excess over Ang II) at 10 µL/min. After
3 hours of infusion, the rats were killed by CO2
inhalation. The aorta from the aortic arch to the renal artery
and the heart ventricles were excised and immediately frozen in
LN2.
Blood Pressure Measurements
Systolic, diastolic, and mean blood
pressures of 10-week-old SHRs (Taconic, Germantown, NY) and
weight-matched Wistar-Kyoto (WKY) control rats were measured by
tail-cuff plethysmography (Ueda Electronics) as described
previously.12 Blood pressure measurements were made before
and after 1-week treatments with either captopril (100 mg ·
kg-1 · d-1; Sigma)
or candesartan-cilexetil TCV-116 (10 mg ·
kg-1 · d-1;
provided by Dr Peter Morsing, Astra Hassle AB) delivered in the
drinking water.
Statistics
All statistical analyses were performed by 1-way ANOVA
with SigmaStat software (Jandel Scientific). Values of
P<0.05 were considered significantly different.
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Results |
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Role of the AT1 Receptor on PAI-1 Expression in RASMCs and in Rat Cardiomyocytes
The effects of angiotensin peptides Ang I (Asp1-Leu10), Ang II (Arg1-Phe8), Ang III (Val2-Phe8), Ang (1-7) (Asp1-Pro7), and Ang IV (Val3-Phe8) on PAI-1 expression in RASMCs were examined and compared. Cells were treated with 100 nmol/L of these peptides for 3 hours followed by RNA isolation and Northern blot analysis of PAI-1 expression, as described previously.9 28 This study demonstrated that Ang I, Ang II, and Ang III were potent stimulators of PAI-1 mRNA expression (Figure 1
). In contrast, Ang IV and Ang
(1-7) did not significantly affect PAI-1 mRNA levels. To examine the
role of the AT1 receptor on PAI-1 gene
expression, cells were pretreated for 15 minutes with 1 µmol/L
of the AT1 antagonist candesartan
followed by stimulation with angiotensin peptides. This
study demonstrated that AT1 antagonism completely
blocked Ang I–, Ang II–, and Ang III–stimulated PAI-1 expression in
RASMCs (Figure 1). To compare the effects of Ang I, Ang II, and
Ang III on PAI-1 expression in RASMCs, cells were stimulated with 1, 5,
10, 50, or 100 nmol/L of Ang I, Ang II, or Ang III for 3 hours.
Northern blot analysis revealed that the
ED50 for Ang II–induced PAI-1 mRNA was 1 nmol/L,
compared with 10 nmol/L for Ang I and Ang III (online
Figure; see www.atvbaha.org).
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The potential effects of Ang II and the AT1
receptor on PAI-1 mRNA expression were also examined in primary culture
of neonatal rat cardiomyocytes. Cells were stimulated with
Ang II (100 nmol/L, 2 hours) in the presence or absence of 1
µmol/L candesartan. Northern blot analysis revealed that Ang
II increased PAI-1 mRNA levels by 4-fold (P<0.001), and
this response was blocked by AT1 antagonism
(Figure 2).
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Effect of Short-Term Intrajugular Ang II Infusion on Aortic and
Cardiac PAI-1 Expression
A possible concern from these in vitro studies is that the effects
of the Ang II/AT1 receptor pathway on PAI-1
expression in RASMCs and cardiomyocytes may not reflect the
role of this pathway in vascular PAI-1 gene expression in vivo. The
effect of short-term Ang II administration on aortic and cardiac PAI-1
expression was examined in awake Sprague-Dawley rats subjected to
continuous Ang II infusion (100 ng ·
kg-1 · 10
µL-1 · min-1)
for 3 hours via an intrajugular catheter. Control animals were infused
with saline at 10 µL/min for 3 hours. After these infusions, the
aorta and ventricles were harvested, and PAI-1 mRNA levels were
examined by Northern blot analyses. This study demonstrated
that Ang II infusion increased aortic and heart PAI-1 mRNA expression
by 17- and 9-fold, respectively, compared with saline infusion (Figure 3). To examine the role of the
AT1 receptor in these Ang II responses,
candesartan (25 µg · kg-1 ·
min-1) was coinfused with Ang II as described
above. This study showed that AT1 antagonism
completely blocked the Ang II–induced PAI-1 expression in both aorta
and ventricles (Figure 3). Candesartan infusion alone did not
affect PAI-1 mRNA levels. These studies show that short-term
administration of Ang II increases aortic and cardiac PAI-1 mRNA
expression and that these effects of Ang II are mediated via the
AT1 receptor.
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Effects of ACE Inhibition and AT1 Antagonism on Aortic
and Cardiac PAI-1 Expression in SHRs and WKY Rats
To determine whether the Ang II/AT1
receptor pathway may also affect vascular PAI-1 expression in
hypertension, the effects of ACE inhibition and
AT1 antagonism on aortic and cardiac PAI-1
expression in SHRs were investigated. The SHR is a genetic model of
hypertension that is sensitive to ACE inhibition and
AT1 antagonism, as well as gene therapies
targeted at RAS inhibition.29 30 Mean blood pressures of
10-week-old SHRs and weight-matched control WKY rats were 142.6±2.8
and 110.9±1.8 mm Hg, respectively (the
Table). Treatment of these SHRs for 1
week with 100 mg · kg-1 ·
d-1 captopril and 10 mg ·
kg-1 · d-1
candesartan TCV-116 reduced mean blood pressure to 123.5±2.9
mm Hg (P=0.031) and 96.5±3.5 mm Hg
(P<0.001), respectively, compared with untreated SHRs.
Treatment of WKY rats with captopril did not significantly affect mean
blood pressure; however, treatment with candesartan reduced mean blood
pressure to 79.8±2.8 (P<0.001; the Table).
Comparison of vascular PAI-1 expression in untreated SHRs and WKY rats
revealed that the aortic and cardiac PAI-1 mRNAs in SHRs were elevated
by 5.8-fold (P<0.05) and 2-fold (P<0.05),
respectively, compared with WKY rats (Figure 4). Treatment of SHRs with captopril or
candesartan similarly reduced aortic PAI-1 mRNA by 94%
(P<0.05, Figure 4). In the heart, candesartan
treatment of SHRs reduced PAI-1 expression by 72% (P<0.05)
compared with untreated SHRs. Captopril treatment of SHRs, at a dose
that reduced aortic PAI-1 expression and mildly reduced mean blood
pressure, did not significantly affect cardiac PAI-1 levels. Neither
captopril nor candesartan significantly altered PAI-1 expression in WKY
rats in these vascular tissues.
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Discussion |
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This report demonstrates that the AT1 receptor pathway mediates the effects of Ang II on PAI-1 gene expression in the rat aorta and heart ventricle. Comparison of the effects of angiotensin peptides on PAI-1 expression in RASMCs revealed that Ang I, Ang II, and Ang III increased PAI-1 mRNA through an AT1-dependent pathway, whereas Ang IV and Ang (1-7) did not affect PAI-1 levels. In addition, we have shown that Ang II–induced PAI-1 expression in cultured cardiomyocytes was mediated by the AT1 receptor. These results are in contrast to those of other studies, which have suggested that the effects of Ang II are mediated by an Ang IV/AT4 pathway.24 The complete blockade of Ang II–induced PAI-1 expression by the AT1-selective antagonist candesartan may be attributed to its higher affinity and slower dissociation kinetics than other AT1 antagonists tested, such as losartan.26 31 Because candesartan reduces maximal Ang II binding to the AT1 receptor, whereas losartan causes a rightward shift in the Ang II dose response without reducing maximal Ang II binding,31 it is likely that the partial reduction of Ang II–induced PAI-1 expression by losartan9 was due to incomplete antagonism of the AT1 receptor. Because RASMCs express ACE-like activity in culture,8 the ability of candesartan to block Ang I–induced PAI-1 expression suggests that Ang I is converted to Ang II, followed by subsequent activation of the AT1 receptor. The observation that Ang III–stimulated PAI-1 expression is also blocked by candesartan is consistent with previous reports that have shown that the N-terminal aspartate of Ang II is not essential for AT1 activation.32 These results suggest that a combination of Ang II and Ang III stimulation of AT1 may contribute to increased vascular PAI-1 mRNA levels. Because aminopeptidase A, a zinc metallopeptidase that converts Ang II to Ang III, is widely expressed and elevated in SHRs,33 it is possible that Ang III may contribute to the effects of the AT1 receptor on vascular PAI-1 expression in vivo. Processing of Ang III to Ang IV by aminopeptidase N would be expected to diminish AT1-induced PAI-1 gene expression. Further characterization of AT4 receptors and development of specific Ang IV antagonists are needed to establish the role of the Ang IV/AT4 pathway on vascular PAI-1 expression.
Coinfusion of candesartan blocked Ang II–induced PAI-1 gene expression in both the rat aorta and heart ventricle. This study has demonstrated that short-term administration of Ang II rapidly induces PAI-1 expression in these vascular tissues and that this Ang II response is mediated by the AT1 receptor. Because previous studies have shown that PAI-1 mRNA expression is correlated with PAI-1 protein synthesis,9 12 it is likely that the AT1-induced changes in PAI-1 mRNA expression result in an increase of PAI-1 protein production and secretion from the vasculature. Although the role of vascular PAI-1 expression in affecting circulating PAI-1 levels is not known, the effects of Ang II and AT1 antagonism on vascular PAI-1 expression described in this study are consistent with reports that have shown that Ang II infusion elevates plasma PAI-1 antigen34 and that ACE inhibition and AT1 antagonism lower plasma PAI-1 in human subjects.13 14 15 35 Although changes in vascular PAI-1 production may affect circulating PAI-1 levels, it is likely that other sites of PAI-1 synthesis, its release from platelets, and its clearance are also major determinants of plasma PAI-1 levels.
Recent studies have shown that plasma PAI-1 levels are positively correlated with blood pressure5 and are reduced in hypertensive subjects after treatment with an ACE inhibitor and AT1 antagonist.7 17 To investigate the potential effect of hypertension on vascular PAI-1 mRNA levels in rats, we compared aortic and cardiac PAI-1 expression in the SHR with that of normotensive WKY control rats. This study demonstrated that PAI-1 expression in these vascular tissues was elevated by 2- to 5-fold in the SHR compared with WKY rats. Furthermore, because candesartan treatment normalized PAI-1 mRNA expression in both the aorta and heart in the SHR, it is likely that the AT1 receptor contributed to the elevated vascular PAI-1 expression in this rat model of essential hypertension. Although Ang II contributes to elevated blood pressure in the SHR, the precise mechanism by which Ang II does so in this model is unknown. Plasma and tissue levels of Ang II appear similar in the SHR and normotensive control rats.36 However, it is possible that local cellular increases in Ang II production contribute to an enhanced Ang II action in an autocrine/paracrine manner. Recent studies have shown that cultured vascular smooth muscle cells from SHRs are capable of generating Ang II, which leads to autocrine stimulation of AT1 receptors, whereas Ang II production was undetectable in vascular smooth muscle cell cultures from WKY rats.37 Alternatively, enhanced pressor sensitivity to Ang II and Ang III may contribute to the increased vascular AT1 action in SHRs.38 39
In summary, this report demonstrates that the effects of Ang II on PAI-1 gene expression in the rat aorta and heart ventricle are mediated by the AT1 receptor. In addition, studies on SHRs suggest that vascular PAI-1 expression is elevated in hypertension and that both AT1 antagonism and ACE inhibition can reduce elevated vascular PAI-1 gene expression in this model. These findings suggest that the RAS influences vascular PAI-1 expression in rats primarily through the Ang II/AT1 pathway.
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants DK 48358 (to E.P.F.) and DK 36836 (Joslin’s Diabetes and Endocrinology Research Center Grant) and grants from the Juvenile Diabetes Foundation International and the Ripple Foundation. H.-C. Chen is a recipient of a Mary K. Iacocca Fellowship.
Received May 31, 2000; accepted June 26, 2000.
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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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 P. Sawathiparnich, L. J. Murphey, S. Kumar, D. E. Vaughan, and N. J. Brown Effect of Combined AT1 Receptor and Aldosterone Receptor Antagonism on Plasminogen Activator Inhibitor-1 J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3867 - 3873. [Abstract] [Full Text] [PDF]
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 Y. Yia, H. Wne, S. Bobst, M.-C. Day, and R. E. Kellems Maternal Autoantibodies From Preeclamptic Patients Active Angiotensin Receptors on Human Trophoblast Cells Reproductive Sciences, February 1, 2003; 10(2): 82 - 93. [Abstract] [PDF]
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N. J. Brown, S. Kumar, C. A. Painter, and D. E. Vaughan ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism: Differential Effects on PAI-1 Over Time Hypertension, December 1, 2002; 40(6): 859 - 865. [Abstract] [Full Text] [PDF]
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 Y. Xia, H. Y. Wen, and R. E. Kellems Angiotensin II Inhibits Human Trophoblast Invasion through AT1 Receptor Activation J. Biol. Chem., June 28, 2002; 277(27): 24601 - 24608. [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. Mustafa, Joo Hyung Lee, Siew Yeen Chai, A. L Albiston, S. G McDowall, and F. A. Mendelsohn Bioactive angiotensin peptides: focus on angiotensin IV Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 205 - 210. [PDF]
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