(Hypertension. 2000;35:43.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Aging and Chronic Hypertension Decrease Expression of Rat Aortic Soluble Guanylyl Cyclase
From the Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt/Main, Germany.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—We analyzed the influence of aging and genetic hypertension on the function and expression of soluble guanylyl cyclase (sGC) in the aortas of prehypertensive and old spontaneously hypertensive rats (SHR) as well as in age-matched normotensive Wistar-Kyoto rats (WKY). The expression of heterodimeric sGC (
1 and ß1) was
assessed at the mRNA and protein level, and its function was assessed
by the relaxant responses of phenylephrine-contracted
endothelium-denuded aortic rings to the nitric oxide
(NO) donor sodium nitroprusside. The vasodilator potency of sodium
nitroprusside was significantly reduced (P<0.05) with
age (3- to 6-fold increase in the EC50 in old WKY and SHR
compared with their young counterparts) as well as with hypertension
(3-fold increase in old SHR compared with age-matched WKY), whereas the
vasodilator potency of sodium nitroprusside did not differ between
young SHR and WKY. A similar influence of aging and hypertension on
NO-stimulated GC activity was revealed at the GC expression level:
Whereas the ß1 protein content was similar in young rats
of both strains, old WKY exhibited 60% lower and old SHR exhibited
80% lower ß1 subunit protein compared with young rats
(P<0.05). Moreover, the abundance of 1
and ß1 mRNA (assessed by reverse
transcriptase—polymerase chain reaction) was similar in young rats but
was 2.5-fold (1) and 4.3-fold (ß1) lower
in old SHR compared with old WKY. In conclusion, our findings show that
both aging and hypertension decrease sGC expression and its
NO-dependent activation in aortic tissue. Downregulation of sGC may
therefore contribute to arterial dysfunction in senescence
and chronic hypertension.
Key Words: aging • hypertension, genetic • guanylyl cyclase • aorta • nitric oxide
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The hemoprotein soluble guanylyl cyclase (sGC) is the predominant intracellular nitric oxide (NO) receptor in vascular smooth muscle cells,1 which mediates NO signaling via formation of cGMP. This enzyme is a heterodimer and consists in most mammalian tissues of
1 (76- to 82-kDa) and
ß1 (70-kDa) protein subunits.2
Aging and chronic hypertension are associated with functional and
morphological changes of the vessel wall, ie, the vascular
endothelium and the smooth muscle.
Endothelial dysfunction is characterized by a decreased
responsiveness to endothelium-dependent
vasodilators.3 Several studies have addressed the
underlying mechanism(s) in different vascular beds at the level of
endothelial NO formation and reported conflicting
results with regard to activity and expression of
endothelial NO synthase and NO
bioavailability.4 5 6 However, endothelial
dysfunction may also result from impaired signaling downstream from NO
in the vascular smooth muscle. Thus, other studies emphasized a
negative influence of aging7 8 9 and
hypertension7 10 11 on the NO responsiveness of vascular
smooth muscle cells. We found recently that compared with aortic rings
of age-matched normotensive Wistar-Kyoto rats (WKY), aortas of
16-month-old genetically spontaneously hypertensive rats (SHR)
exhibited a reduced vasodilator responsiveness to acetylcholine and
sodium nitroprusside (SNP), although the expression of
endothelial NO synthase protein and mRNA was not
different between both strains.12 This finding suggested
an impairment of NO-dependent vasodilator function either at the level
of or downstream from sGC. Indeed, we observed a lower content of
immunoreactive sGC ß1 protein in aortic tissue
of senescent SHR compared with age-matched WKY.12 The
objective of the present study was to assess the influence of age
on the expression and NO-dependent function of sGC in the aorta of
normotensive and genetically hypertensive rats. |
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Materials
Bradford reagent was purchased from Bio-Rad; guanidine thiocyanate, from Sigma; reverse transcriptase and agarose, from GIBCO-BRL; and Tween 20, from Serva. Oligodeoxythymidine and Taq polymerase were from Pharmacia Biotech. All other chemicals were bought from Roth. The polyclonal peptide antibody directed against the ß1 subunit of the rat lung sGC was kindly provided by Dr Peter Yuen, Memphis, Tenn.13
Animals
Investigations were performed with isolated aortic rings from
2-month-old prehypertensive and 16-month-old hypertensive male SHR and
normotensive age-matched male WKY (n=7 in each age and strain group, 28
rats in total). SHR and WKY were purchased from Möllegaard
(Skensved, Denmark) at the age of 1 month, when they exhibited equal
body weights (75±5 g) and systolic blood pressures (SBPs). SBP
was measured in conscious rats by tail plethysmography under light
anesthesia. The investigation conforms with the Guide for
the Care and Use of Laboratory Animals published by the US National
Institutes of Health (NIH publication No. 85–23, revised
1985).
Vasodilator Responsiveness of Preconstricted Aortic Rings
The thoracic aorta was isolated from anesthetized (60
mg/kg pentobarbital IP) rats, cleaned of connective tissue, cut into
rings of equal length (3 mm), and mechanically
deendothelialized. One aortic ring was
immediately frozen in liquid nitrogen for measurements of the mRNA and
protein levels of sGC. Other rings (2) were mounted in an organ bath
(Schuler-Organbad, Hugo Sachs Electronic) and suspended in
Krebs-Henseleit solution (pH 7.4, 37°C) for measurements of isometric
contractile force. The rings were equilibrated for 30 minutes under a
resting tension of 2.5 g (achieved by 0.5-g steps) in
carbogen-gassed (95% O2/5%
CO2) Krebs-Henseleit buffer12 in the
presence of diclofenac (1 µmol/L). Rings were preconstricted 2
times with 60 mmol/L potassium and thereafter with 1 µmol/L
phenylephrine (PE). After development of a stable
contraction to PE, the relaxant response to increasing cumulative
concentrations of SNP (0.3 nmol/L to 1 µmol/L) was
determined.
Isolation of Total RNA From Rat Aorta and RT-PCR of
1 and ß1 sGC mRNA
The total RNA was extracted from aortic tissue ground in liquid
nitrogen by the modified guanidine isothiocyanate method of Chomczynski
and Sacchi.14 Total RNA (2 µg) was incubated with 200 U
reverse transcriptase (RT), deoxy nucleotides (dNTPs,
125 µmol/L), 200 ng oligodeoxythymidine (dT), and reaction
buffer in a final volume of 20 µL at 37°C for 1 hour. Published
sequences15 were used to synthesize primers for the sGC
1 subunit (forward, base position 1527
5'-GAAATCTTCAAGGGTTATG-3'; reverse, base position 2335
5'-GACTGTCCTGGCTTTGTG-3'), ß1 subunit (forward,
base position 1491 5'-GGTTTGCCAGAACCTTGTATCCACC3'; reverse, base
position 1750 5'-GGTGTCTCATGTCCCCAGAAAACTC-3'), and elongation factor
II (forward, base position 1021 5'-GACATCACCAAGGGTGTGCAG-3'; reverse,
base position 1204 5'-GCGGTCAGCACACTGGCATA-3'). cDNA (5 µL) was
amplified (20 cycles for elongation factor II, 25 cycles for
ß1 subunit, and 35 cycles for
1 subunit) at 94°C for 1 minute
(denaturation), at 54°C to 58°C for 1.5 minutes (annealing), and at
72°C for 1.5 minutes (elongation). The final step was completed with
7 minutes of elongation at 72°C. The cDNA was amplified with 10 pmol
of each primer, 2.5 U Taq polymerase, dNTPs (200 µmol/L), and
MgCl2 containing reaction buffer (50 µL final
volume). Ten microliters of this mixture was electrophoresed on a 1.5%
agarose gel, stained with ethidium bromide, and visualized on a UV
transilluminator. Fluorescent bands were recorded by means
of a fluorescent light–sensitive video camera, and negatives
were evaluated by scanning densitometry (SCION IMAGE BETA II).
Polymerase chain reaction (PCR) product sizes of the elongation
factor II (225 bp), sGC 1 subunit (826 bp),
and ß1 subunit (284 bp) were controlled by use
of DNA standards. With 0.5 µg to 2.5 µg total RNA, a linear
increase in optical density (correlation coefficients
r=0.998 for 1, r=0.995
for ß1, and r=0.969 for elongation
factor II) was obtained between 20 to 35 cycles
(ß1 and elongation factor II) and 30 to 40
cycles (1).
Immunodetection of sGC ß1 Protein in Rat
Aorta
Total protein was precipitated by alcohol from the phenol phase
of the RNA extraction. Proteins (50 µg per lane) were separated on
Laemmli gels and electroblotted. The blots were blocked at 4°C
overnight and then incubated for 2 hours at room temperature with a
polyclonal peptide antibody directed against the
ß1 subunit of rat sGC (1:1000 dilution in
blocking buffer). The blots were washed and incubated with a
peroxidase-linked anti-rabbit IgG, and immunoreactive protein bands
were visualized by chemiluminescence and exposure to x-ray film. The
autoradiographs were analyzed by scanning densitometry. To
check for equal protein loading and transfer, Ponceau staining and
-actin immunostaining were performed with stripped
blots.
Statistics
Data are expressed as mean±SEM of n rats. Direct comparisons
between 2 animal groups (RT-PCR and Western blot) were performed by the
Student t test. A value of P<0.05 was considered
significant. Relaxant responses were expressed as percent relaxation
relative to the level of precontraction. EC50
values were estimated by fitting individual concentration-relaxation
curves to a 3-parameter logistic equation by use of
nonlinear regression analysis (Slide Write Plus software).
Differences between EC50 values were tested by
1-way ANOVA, followed by the Tukey correction for multiple comparisons
(Instat software).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
SBP and Body Weight of SHR and WKY
The 16-month-old SHR presented a significantly higher mean SBP than did age-matched normotensive WKY (Table 1). The 2-month-old prehypertensive SHR also exhibited a higher SBP than did young WKY; however, the difference between the young rats was less marked than between the old rats. Furthermore, the body weight was significantly higher in WKY than in age-matched SHR (Table 1).
|
Influence of Aging and Chronic Hypertension on Vasodilator
Responses to SNP
The NO donor SNP applied in cumulative concentrations (0.3 nmol/L
to 1 µmol/L) elicited a concentration-dependent relaxation of
endothelium-denuded PE (1 µmol/L)–contracted
aortic rings of all animal groups studied. Complete offset of active
tension (100% relaxation) was obtained in each group at the highest
concentration of SNP applied (1 µmol/L) (Figure 1). However, the vasodilator potency of
SNP was significantly decreased in aortas of old WKY
(EC50 3±0.3 nmol/L) compared with their young
counterparts (EC50 1.0±0.2 nmol/L, n=6). The
vasodilator potency of SNP was similar in prehypertensive young SHR
(EC50 1.5±0.2 nmol/L) and normotensive young
WKY. These findings indicate a significant influence of age on
NO-induced vasorelaxation.
|
) SHR and young (
) and old (
)
normotensive WKY. Results (% relaxation) are mean±SEM from 12 aortic
rings from 6 different rats per group.In addition, chronic hypertension was associated with a further loss of SNP responsiveness independent of age. Thus, the EC50 for SNP-induced aortic relaxation was 3-fold higher (9±1 nmol/L, n=6) in old SHR than in old WKY (Figure 1). These results suggest that genetic hypertension and age are associated with a defect in NO-dependent smooth muscle relaxation at the level of or downstream from sGC.
Influence of Aging and Hypertension on Expression of sGC
1 and ß1 mRNA
To clarify whether the reduction in nitrovasodilator potency by
aging and hypertension was due to a reduced expression of sGC, total
RNA was extracted from rat aortas, and sGC mRNA was amplified by RT-PCR
using specific oligonucleotide primers for
1 and ß1 subunits.
According to densitometric analysis of the RT-PCR products
of 1 (826-bp) and ß1
(284-bp) subunits, the abundance of both transcripts was similar
between young SHR and age-matched WKY (Figure 2A and 2B, and Table 2) but was significantly lower in old SHR
(1 67% and ß1 57%)
and old WKY (1 80% and
ß1 70%) than in young rats (Figure 2C and 2D, Figure 3A and 3B, and Table 2). In contrast, the mRNA levels of elongation factor II were
not significantly different in both young and old SHR and WKY (Figures 2 and 3). This finding shows that age is associated with
a reduced expression of sGC subunit mRNAs in rat aorta and thus
provides an explanation for the age-dependent loss in nitrovasodilator
responsiveness of these blood vessels (Figure 1). Furthermore,
the expression of both sGC transcripts was influenced by chronic
hypertension independent of age. It was 2.5-fold
(1 mRNA) and 4-fold
(ß1 mRNA) lower in old SHR than in old WKY
(Figure 3C and 3D). As summarized in Table 2, these
results provide a rationale for the loss in NO-dependent sGC function
in the rat aorta by age and chronic hypertension.
|
|
|
Influence of Aging and Chronic Hypertension on Expression of
sGC Protein
Finally, to investigate whether the reduced mRNA levels are
translated into reduced expression of sGC protein, the concentration of
the sGC ß1 subunit was determined by Western
blot analysis. Immunoblotting of total protein
extracts from rat aortic tissue with a polyclonal antibody raised
against the ß1 subunit of sGC revealed 2
positive bands, one that comigrated with the single 70-kDa band of the
ß1 subunit of purified sGC from bovine lung
used as a standard and another (unspecific) that migrated at 45 kDa
(not shown). The densitometric analysis of the 70-kDa band
revealed no difference in the ß1 protein
content between young SHR and WKY (Figure 4A). However, the expression of the
ß1 subunit was markedly reduced in old SHR and
WKY compared with young rats of either strain (Figure 4B and 4C), thus confirming that the age-induced loss of nitrovasodilator
responsiveness is due to decreased sGC protein expression. There was
also a significant decrease in the ß1 protein
content in old SHR compared with old WKY (Figure 4D).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
To identify the role of the NO receptor sGC in vascular dysfunction associated with aging and chronic hypertension, we assessed NO donor–dependent (SNP-dependent) relaxations and expression of sGC mRNA and protein in aortic tissue of senescent and young SHR and their normotensive counterparts, age-matched WKY.
We observed a downregulation of sGC expression at the mRNA
(1 and ß1 transcripts)
and protein (ß1 subunit) levels induced by
aging (old versus young WKY). Consistently, the decreased
aortic sGC expression in senescent WKY and SHR translated functionally
into a blunted vasodilator response of
endothelium-denuded PE-contracted aortic rings to SNP
(Figure 1). Strain differences did not account for the effect of
aging, in view of the fact that prehypertensive young SHR and
age-matched WKY exhibited similar sGC expression and NO vasodilator
responsiveness. This is in accordance with previous reports of a normal
nitrovasodilator response and NO formation in conduit and resistance
vessels of SHR before the onset of hypertension.6 7 Our
finding of a reduced aortic sGC expression in senescent WKY also
provides an explanation for the decreased SNP-induced relaxation of
aortas from aged Wistar rats observed previously.7 8 Thus,
it appears that aging worsens the NO-dependent vasodilator mechanism of
the rat aorta not only by eliciting endothelial
dysfunction (ie, decreasing agonist-induced endothelial
NO release and bioavailability)5 but also by decreasing
the expression of sGC in aortic smooth muscle cells. Interestingly,
aging also decreases nitrovasodilator responsiveness of nonvascular
smooth muscle in guinea pigs,16 suggesting that
downregulation of vascular and nonvascular smooth muscle sGC may be a
common response to aging throughout the animal species.
Furthermore, we demonstrated that in addition to aging, chronic hypertension decreases sGC expression in the rat aorta at the mRNA level, thus corroborating our previous observation of a lower sGC protein level in aortic tissue of aged SHR compared with aged WKY.12 This finding is in line with the loss of nitrovasodilator responsiveness in hypertensive SHR observed by other investigators9 11 and the reduced sGC activity in lung homogenates of old SHR.17 However, it is still unclear whether hypertensive patients suffer from reduced vascular sGC expression in addition to endothelial dysfunction. Either reduced10 or unaltered18 forearm blood flow responses to nitrovasodilators have been observed. Interestingly, sGC subunit gene loci cosegregate with blood pressure–controlling genes in Dahl rats with salt-sensitive hypertension.19
In apparent conflict with the present findings, in one recent study the level of sGC ß1 mRNA (detected by Northern blot) in cultured aortic smooth muscle cells from hypertensive (14-week-old) SHR was found to be 2-fold higher than in cultured cells from age-matched WKY.20 In that study the cGMP response to NO donors was higher in cultured cells and aortic rings from SHR compared with WKY, whereas there was no difference in NO responsiveness between cultured cells from prehypertensive 5- to 6-week-old SHR and normotensive WKY. One explanation for the discrepancy with our findings is that smooth muscle cells change their phenotype in culture and therefore do not express the same protein pattern as in the vessel wall in situ. However, we cannot exclude the possibility that sGC expression differs between adult (14-week-old) and more aged (16-month-old) SHR.
The mechanisms underlying the reduced expression of sGC in
chronic hypertension and aging are still unknown. Several conditions
that lead to decreased sGC protein expression have been identified in
vitro: In cultured cells, cAMP-eliciting agonists15 21 and
exposure to high NO levels, achieved either by
nitrovasodilators22 23 or by cytokine-elicited NO
synthase II,24 reduce the stability of the sGC
1 and ß1 mRNA.
Furthermore, nerve growth factor reduces the abundance of
ß1 mRNA in PC-12 cells via a
p21ras-dependent pathway.25
Adaptation to hypertension promotes morphological changes in the aorta
characterized by wall thickening due to media hypertrophy,
and enhanced levels of various growth factors seem to account for this
adaptive morphological response. For instance, SHR exhibit increased
plasma levels of endothelin-1,26 angiotensin
II, thrombin, and platelet-derived growth factor,27
all of which stimulate proliferation of rat aortic vascular smooth
muscle cells via activation of
p21ras.28 It is tempting to
speculate that growth signals in general decrease the expression of sGC
in smooth muscle cells.
We have shown that aging and chronic hypertension decrease the expression of sGC at the mRNA and protein level, thus attenuating NO-dependent vasodilator function in aortas of senescent WKY and SHR. The reduced NO-dependent vasodilator capacity at the level of the vascular smooth muscle will contribute to vascular dysfunction in aging and hypertension, in addition to endothelial dysfunction.
|
Acknowledgments |
|---|
We appreciate the skillful technical assistance by Ussmann Jaffer and thank Drs G. Wiemer and H. Rütten (PGU Cardiovascular Agents, Hoechst Marion Roussel, Frankfurt/Main) for providing the senescent SHR and WKY.
|
Footnotes |
|---|
Reprint requests to Alexander Mülsch, PhD, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
Received June 25, 1999; first decision July 13, 1999; accepted August 17, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–142.[Medline] [Order article via Infotrieve]
2.
Nakane M, Arai K, Saheki S, Kuno T, Buechler W, Murad
F. Molecular cloning and expression of cDNAs coding for soluble
guanylate cyclase from rat lung. J Biol
Chem. 1990;265:16841–16845.
3.
Dominiczak AF, Bohr DF. Nitric oxide and its putative
role in hypertension. Hypertension. 1995;25:1202–1211.
4.
Higashi Y, Oshima T, Ozono R, Matsuura H, Kajiyama G.
Aging and severity of hypertension attenuate
endothelium-dependent renal vascular relaxation in
humans. Hypertension. 1997;30:252–258.
5. Tschudi MR, Barton M, Bersinger NA, Moreau P, Cosentino F, Noll G, Malinski T, Lüscher TF. Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery. J Clin Invest. 1996;98:899–905.[Medline] [Order article via Infotrieve]
6.
Chou TC, Yen MH, Li CY, Ding YA. Alterations of nitric
oxide synthase expression with aging and hypertension in rats.
Hypertension. 1998;31:643–648.
7.
Shirasaki Y, Su C, Lee TJ, Kolm P, Cline WH, Nickols
GA. Endothelial modulation of vascular relaxation to
nitrovasodilators in aging and hypertension. J Pharmacol Exp
Ther. 1986;239:861–866.
8. Moritoki H, Tanioka A, Maeshiba Y, Iwamoto T, Ishida Y, Araki H. Age-associated decrease in histamine-induced vasodilation may be due to reduction of cyclic GMP formation. Br J Pharmacol. 1988;95:1015–1022.[Medline] [Order article via Infotrieve]
9. Teravainen TL, Mervaala EM, Porsti I, Laakso J, Vapaatalo H, Karppanen H. Influence of age and dietary sodium on the cardiovascular and renal effects of ramipril in spontaneously hypertensive rats. Methods Find Exp Clin Pharmacol. 1997;19:311–321.[Medline] [Order article via Infotrieve]
10. Robinson BF, Dobbs RJ, Bayley S. Response of forearm resistance vessels to verapamil and sodium nitroprusside in normotensive and hypertensive men: evidence for a functional abnormality of vascular smooth muscle in primary hypertension. Clin Sci. 1982;63:33–42.[Medline] [Order article via Infotrieve]
11.
Mourlon-Le Grand MC, Benessiano J, Levy BI. cGMP
pathway and mechanical properties of carotid artery wall in WKY rats
and SHR: role of endothelium. Am J
Physiol. 1992;263:H61–H67.
12.
Bauersachs J, Bouloumié A, Mülsch A, Wiemer
G, Fleming I, Busse R. Vasodilator dysfunction in aged spontaneously
hypertensive rats: changes in NO synthase III and soluble guanylyl
cyclase expression, and in superoxide anion production.
Cardiovasc Res. 1998;37:772–779.
13.
Yuen PST, Doolittle KL, Garbers DL. Dominant negative
mutants of nitric oxide-sensitive guanylyl cyclase. J Biol
Chem. 1994;269:791–793.
14. Chromczynski P, Sacchi N. Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159.[Medline] [Order article via Infotrieve]
15.
Papapetropoulos A, Marczin N, Mora G, Milici A, Murad
F, Catravas JD. Regulation of vascular smooth muscle soluble
guanylate cyclase activity, mRNA, and protein levels by
cAMP-elevating agents. Hypertension. 1995;26:696–704.
16. Wheeler MA, Pontari M, Dokita S, Nishimoto T, Cho YH, Hong KW, Weiss RM. Age-dependent changes in particulate and soluble guanylyl cyclase activities in urinary tract smooth muscle. Mol Cell Biochem. 1997;169:115–124.[Medline] [Order article via Infotrieve]
17. Kojda G, Kottenberg K, Hacker A, Noack E. Alterations of the vascular and myocardial guanylate cyclase/cGMP-system induced by long-term hypertension in rats. Pharm Acta Helv. 1998;73:27–35.[Medline] [Order article via Infotrieve]
18. Panza J. A, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–24.[Abstract]
19.
Azam M, Gupta G, Chen W, Wellington S, Warburton
D, Danzinger RS. Genetic mapping of soluble guanylyl cyclase genes:
implications for linkage to blood pressure in the Dahl rat.
Hypertension. 1998;32:149–154.
20.
Papapetropoulos A, Marczin N, Snead MD, Cheng C, Milici
A, Catravas JD. Smooth muscle cell responsiveness to nitrovasodilators
in hypertensive and normotensive rats. Hypertension. 1994;23:476–484.
21.
Shimouchi A, Janssens SP, Bloch DB, Zapol WM, Bloch KD.
cAMP regulates soluble guanylate cyclase
ß1-subunit gene expression in RFL-6 rat fetal
lung fibroblasts. Am J Physiol. 1993;265:L456–L461.
22.
Ujiie K, Hogarth L, Danzinger R, Drewett JG, Yuen PST,
Pang IH, Star RA. Homologous and heterologous desensitization of
guanylyl cyclase-linked nitric oxide receptor in cultured rat medullary
interstitial cells. J Pharmacol Exp Ther. 1994;270:761–764.
23. Papapetropoulos A, Go CY, Murad F, Catravas JD. Mechanisms of tolerance to sodium nitroprusside in rat cultured aortic smooth muscle cells. Br J Pharmacol. 1996;117:147–155.[Medline] [Order article via Infotrieve]
24. Papapetropoulos A, Abou-Mohamed G, Marczin N, Murad F, Caldwell RW, Catravas JD. Downregulation of nitrovasodilator-induced cyclic GMP accumulation in cells exposed to endotoxin or interleukin-1 beta. Br J Pharmacol. 1996;118:1359–1366.[Medline] [Order article via Infotrieve]
25.
Liu H, Force T, Bloch KD. Nerve growth factor decreases
soluble guanylate cyclase in rat pheochromocytoma PC12
cells. J Biol Chem. 1997;272:6038–6043.
26. Thibault G, Arguin C, Garcia R. Cardiac endothelin-1 content and receptor subtype in spontaneously hypertensive rats. J Mol Cell Cardiol. 1995;27:2327–2336.[Medline] [Order article via Infotrieve]
27. Sarzani R, Brecher P, Chobanian AV. Growth factor expression in aorta of normotensive and hypertensive rats. J Clin Invest. 1989;83:1404–1408.
28. Schieffer B, Drexler H, Ling BN, Marrero MB. G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras. Am J Physiol. 1997;272:2019–1030.
This article has been cited by other articles:
 |
|
 |
|
  S. Meurer, S. Pioch, T. Pabst, N. Opitz, P. M. Schmidt, T. Beckhaus, K. Wagner, S. Matt, K. Gegenbauer, S. Geschka, et al. Nitric Oxide-Independent Vasodilator Rescues Heme-Oxidized Soluble Guanylate Cyclase From Proteasomal Degradation Circ. Res., July 2, 2009; 105(1): 33 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Ruiz-Torres, M. Griera, A. Chamorro, M. L. Diez-Marques, D. Rodriguez-Puyol, and M. Rodriguez-Puyol Tirofiban increases soluble guanylate cyclase in rat vascular walls: pharmacological and pathophysiological consequences Cardiovasc Res, April 1, 2009; 82(1): 125 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Maron, Y.-Y. Zhang, D. E. Handy, A. Beuve, S.-S. Tang, J. Loscalzo, and J. A. Leopold Aldosterone Increases Oxidant Stress to Impair Guanylyl Cyclase Activity by Cysteinyl Thiol Oxidation in Vascular Smooth Muscle Cells J. Biol. Chem., March 20, 2009; 284(12): 7665 - 7672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T. Schermuly, J-P. Stasch, S. S. Pullamsetti, R. Middendorff, D. Muller, K-D. Schluter, A. Dingendorf, S. Hackemack, E. Kolosionek, C. Kaulen, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension Eur. Respir. J., October 1, 2008; 32(4): 881 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Marro, C. Peiro, C. M. Panayiotou, R. S. Baliga, S. Meurer, H. H. H. W. Schmidt, and A. J. Hobbs Characterization of the Human {alpha}1{beta}1 Soluble Guanylyl Cyclase Promoter: KEY ROLE FOR NF-{kappa}B(p50) AND CCAAT-BINDING FACTORS IN REGULATING EXPRESSION OF THE NITRIC OXIDE RECEPTOR J. Biol. Chem., July 18, 2008; 283(29): 20027 - 20036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. G. Sharina, F. Jelen, E. P. Bogatenkova, A. Thomas, E. Martin, and F. Murad {alpha}1 Soluble Guanylyl Cyclase (sGC) Splice Forms as Potential Regulators of Human sGC Activity J. Biol. Chem., May 30, 2008; 283(22): 15104 - 15113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Xia, C. Dimitropoulou, J. Zeng, G. N. Antonova, C. Snead, R. C. Venema, D. Fulton, S. Qian, C. Patterson, A. Papapetropoulos, et al. Chaperone-dependent E3 ligase CHIP ubiquitinates and mediates proteasomal degradation of soluble guanylyl cyclase Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3080 - H3087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Jiang and S. S Stojilkovic Molecular cloning and characterization of {alpha}1-soluble guanylyl cyclase gene promoter in rat pituitary cells J. Mol. Endocrinol., December 1, 2006; 37(3): 503 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dumitrascu, N. Weissmann, H. A. Ghofrani, E. Dony, K. Beuerlein, H. Schmidt, J.-P. Stasch, M. J. Gnoth, W. Seeger, F. Grimminger, et al. Activation of Soluble Guanylate Cyclase Reverses Experimental Pulmonary Hypertension and Vascular Remodeling Circulation, January 17, 2006; 113(2): 286 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Agullo, D. Garcia-Dorado, N. Escalona, M. Ruiz-Meana, M. Mirabet, J. Inserte, and J. Soler-Soler Membrane association of nitric oxide-sensitive guanylyl cyclase in cardiomyocytes Cardiovasc Res, October 1, 2005; 68(1): 65 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Krumenacker, A. Kots, and F. Murad Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase {alpha}1 gene regulation and cGMP synthesis Am J Physiol Cell Physiol, October 1, 2005; 289(4): C778 - C784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Wolin Loss of Vascular Regulation by Soluble Guanylate Cyclase Is Emerging as a Key Target of the Hypertensive Disease Process Hypertension, June 1, 2005; 45(6): 1068 - 1069. [Full Text] [PDF]
|
|
|
|
|
|
S. Kloss, D. Rodenbach, R. Bordel, and A. Mulsch Human-Antigen R (HuR) Expression in Hypertension: Downregulation of the mRNA Stabilizing Protein HuR in Genetic Hypertension Hypertension, June 1, 2005; 45(6): 1200 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. C. Browner, N. B. Dey, K. D. Bloch, and T. M. Lincoln Regulation of cGMP-dependent Protein Kinase Expression by Soluble Guanylyl Cyclase in Vascular Smooth Muscle Cells J. Biol. Chem., November 5, 2004; 279(45): 46631 - 46636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kloss, R. Srivastava, and A. Mulsch Down-Regulation of Soluble Guanylyl Cyclase Expression by Cyclic AMP Is Mediated by mRNA-Stabilizing Protein HuR Mol. Pharmacol., June 1, 2004; 65(6): 1440 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Li, A. K. Reddy, L. N. Ochoa, T. T. Pham, C. J. Hartley, L. H. Michael, M. L. Entman, and G. E. Taffet Effect of Age on Peripheral Vascular Response to Transverse Aortic Banding in Mice J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2003; 58(10): B895 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. G. Sharina, E. Martin, A. Thomas, K. L. Uray, and F. Murad CCAAT-binding factor regulates expression of the {beta}1 subunit of soluble guanylyl cyclase gene in the BE2 human neuroblastoma cell line PNAS, September 30, 2003; 100(20): 11523 - 11528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Friebe and D. Koesling Regulation of Nitric Oxide-Sensitive Guanylyl Cyclase Circ. Res., July 25, 2003; 93(2): 96 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Ndisang, L. Wu, W. Zhao, and R. Wang Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats Blood, May 15, 2003; 101(10): 3893 - 3900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kloss, H. Furneaux, and A. Mulsch Post-transcriptional Regulation of Soluble Guanylyl Cyclase Expression in Rat Aorta J. Biol. Chem., January 17, 2003; 278(4): 2377 - 2383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Lamireau, A. M. Nuyt, X. Hou, S. Bernier, M. Beauchamp, F. Gobeil Jr, I. Lahaie, D. R. Varma, and S. Chemtob Altered Vascular Function in Fetal Programming of Hypertension Stroke, December 1, 2002; 33(12): 2992 - 2998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Ndisang, W. Zhao, and R. Wang Selective Regulation of Blood Pressure by Heme Oxygenase-1 in Hypertension Hypertension, September 1, 2002; 40(3): 315 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sinnaeve, J.-D. Chiche, H. Gillijns, N. Van Pelt, D. Wirthlin, F. Van de Werf, D. Collen, K. D. Bloch, and S. Janssens Overexpression of a Constitutively Active Protein Kinase G Mutant Reduces Neointima Formation and In-Stent Restenosis Circulation, June 18, 2002; 105(24): 2911 - 2916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.M. Vanhoutte Ageing and endothelial dysfunction Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A8 - A17. [Abstract] [PDF]
|
|
|
|
|
|
J. Bauersachs, I. Fleming, D. Fraccarollo, R. Busse, and G. Ertl Prevention of endothelial dysfunction in heart failure by vitamin E: Attenuation of vascular superoxide anion formation and increase in soluble guanylyl cyclase expression Cardiovasc Res, August 1, 2001; 51(2): 344 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mulsch, M. Oelze, S. Kloss, H. Mollnau, A. Topfer, A. Smolenski, U. Walter, J.-P. Stasch, A. Warnholtz, U. Hink, et al. Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta Circulation, May 1, 2001; 103(17): 2188 - 2194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Takata, G. Filippov, H. Liu, F. Ichinose, S. Janssens, D. B. Bloch, and K. D. Bloch Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms Am J Physiol Lung Cell Mol Physiol, February 1, 2001; 280(2): L272 - L278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sinnaeve, J.-D. Chiche, Z. Nong, O. Varenne, N. Van Pelt, H. Gillijns, D. Collen, K. D. Bloch, and S. Janssens Soluble Guanylate Cyclase {{alpha}}1 and {beta}1 Gene Transfer Increases NO Responsiveness and Reduces Neointima Formation After Balloon Injury in Rats via Antiproliferative and Antimigratory Effects Circ. Res., January 19, 2001; 88(1): 103 - 109. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||