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Hypertension. 1995;25:105-109

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(Hypertension. 1995;25:105-109.)
© 1995 American Heart Association, Inc.

Articles

ß-Adrenergic Receptors and Angiotensinogen Gene Expression in Mouse Hepatoma Cells In Vitro

Ming Ming; Jie Wu; Silvana Lachance; Aline Delalandre; Serge Carrière; John S. D. Chan

From the University of Montreal, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada.


*    Abstract
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 *Abstract
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Abstract We have previously reported that addition of 8-bromo-cyclic AMP enhances the stimulatory effect of dexamethasone on the expression of the angiotensinogen gene in mouse hepatoma cells in vitro. Isoproterenol is known to stimulate the synthesis of hepatic intracellular cyclic AMP via ß-adrenergic receptors. To study the possible effect of ß-adrenergic receptors on the expression of the angiotensinogen gene in mouse hepatoma cells, we transiently transfected them with a fusion gene with the 5'-flanking region of the angiotensinogen gene linked to a bacterial chloramphenicol acetyltransferase coding sequence as a reporter, pOCAT (ANG N-1498/+18). The addition of isoproterenol (10-9 to 10-5 mol/L) alone had no stimulatory effect on the expression of pOCAT (ANG N-1498/+18). In the presence of dexamethasone (10-6 mol/L), however, isoproterenol enhanced the stimulatory effect of the dexamethasone on the expression of pOCAT (ANG N-1498/+18). The enhancing effect of isoproterenol was inhibited by the presence of propranolol (ß1- and ß2-adrenergic receptor antagonist) and ICI 118,551 (ß2-adrenergic receptor antagonist) but not by the presence of atenolol (ß1-adrenergic receptor antagonist). Furthermore, the addition of Rp-cAMP (an inhibitor of protein kinase A I and II) blocked the enhancing effect of isoproterenol. These studies demonstrated that isoproterenol enhances the stimulatory effect of dexamethasone on the expression of the angiotensinogen gene in mouse hepatoma cells via ß2-adrenergic receptor and cyclic AMP–dependent protein kinase pathways. Our data may be important in understanding the molecular mechanism(s) of the stimulatory effect of catecholamines/glucocorticoid-induced expression of the angiotensinogen gene in the liver.


Key Words: ß-adrenergic receptors • angiotensinogen gene • hepatoma cells


*    Introduction
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 *Introduction
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Circulating angiotensinogen (ANG) is synthesized mainly in the liver and cleaved successively by renin and angiotensin-converting enzyme to yield the bioactive peptide angiotensin II (Ang II). Recent studies by Kimura et al1 and Fukamizu et al2 demonstrated that transgenic mice that carry an exogenous ANG gene and/or renin gene and express high levels of plasma ANG and Ang II will develop high blood pressure. These studies demonstrated unequivocally that ANG is an important component for the development of hypertension.

We have previously reported the expression of the ANG gene in mouse hepatoma (Hepa 1-6) cells and shown that dexamethasone stimulates the expression of the fusion genes containing the 5'-flanking region of the rat ANG gene fused with a bacterial chloramphenicol acetyltransferase (CAT) coding sequence as reporter in a dose-dependent manner.3 Furthermore, we have shown that addition of 8-bromo-cyclic AMP (8-Br-cAMP) enhanced the stimulatory effect of dexamethasone on the expression of angiotensinogen–chloramphenicol acetyl transferase (ANG-CAT) fusion genes. The addition of 8-Br-cAMP alone, however, had no stimulatory effect on the expression of the ANG-CAT fusion genes. These studies suggest that dexamethasone and cAMP might act synergistically or cooperatively to stimulate the expression of the ANG gene in the liver.

A classic example of the activation of the membrane adenylate cyclase system to increase intracellular cAMP in the liver is seen with catecholamines. Catecholamines (norepinephrine and epinephrine) are known to interact with both {alpha}- and ß-adrenergic receptors.4 5 6 ß-Adrenergic receptors are linked through a guanine nucleotide regulatory protein to adenylate cyclase on the inner part of the plasma membrane of target cells.7 8 The biological responses to interaction of isoproterenol (a ß1- and ß2-adrenergic receptor agonist) are generally mediated by an increase of intracellular cAMP, which subsequently initiates the biochemical cascade, including glycogenolysis in the liver.9 10 11 12 It is not clear, however, whether isoproterenol has an effect on the expression of the ANG gene in the liver.

ß-Adrenergic receptors are present in mouse liver.13 The objective of our present study was to investigate whether addition of isoproterenol enhances the stimulatory effect of dexamethasone on the expression of ANG-CAT fusion genes, pOCAT (ANG N-1498/+18) in Hepa 1-6 in vitro. Our studies provide evidence that isoproterenol enhances the effect of dexamethasone and that the enhanced effect of isoproterenol is mediated via the ß2-adrenergic receptor and the cAMP-dependent protein kinase A pathway.


*    Methods
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 *Methods
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Materials
Both restriction and modifying enzymes were purchased either from Bethesda Research Laboratories, Boehringer-Mannheim, or Pharmacia Inc.

The expression vectors (pOCAT and pRSVCAT containing the coding sequence for CAT without or with Rous sarcoma virus enhancer/promoter sequence fused to the 5' end of the CAT coding sequence, respectively) were a gift from Dr Joel F. Habener (Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston).

{alpha}-[35S]dATP (>1000 Ci/mmol), {alpha}-[32P]CTP (800 Ci/mmol), {gamma}-[32P]ATP (3000 Ci/mmol), and D-threo-[1,214C]-chloramphenicol were purchased from New England Nuclear, Dupont.

R(-)-Isoproterenol(+)-bitartrate salt, S(-)-propranolol hydrochloride, S(-)-atenolol, ICI-118,551 HCl, and Rp-cAMP (an inhibitor of the cAMP-dependent protein kinase A I and II14 ) were all purchased from Research Biochemicals Inc.

Thin-layer chromatography plates were purchased from Fisher Scientific Ltd. Other reagents were molecular-biology grade and were obtained from Sigma Chemical Co, Bethesda Research Laboratories, Boehringer-Mannheim, or Pharmacia Inc.

Construction of Fusion Genes
The method of construction of ANG-CAT fusion genes has been described previously.15 The sequences and orientation for all fusion genes were confirmed by dideoxy sequencing16 with SP6 primers (Promega-Fisher, Inc) and restriction enzyme digestion mapping.

Cell Culture
The mouse hepatoma (Hepa 1-6) cell line was obtained from the American Type Culture Collection. The Hepa 1-6 cells were grown in 100x20-mm plastic Petri dishes (Gibco) using Dulbecco's modified Eagle medium (DMEM), pH 7.20, supplemented with 10% fetal bovine serum (FBS), 50 U/mL penicillin, and 50 µg/mL streptomycin. The cells were incubated in a humidified atmosphere of 95% O2 and 5% CO2 at 37°C. For subculturing, cells were trypsinized (0.05% trypsin and EDTA) and plated at 3.5x105 cells per dish.

DNA Transfection
Plasmid or ANG-CAT fusion gene was transfected into Hepa 1-6 cells using calcium phosphate endocytosis as described previously.3 We have shown previously that the optimal dose of DNA for gene transfection is 20 µg per 0.5 to 1x106 cells. Thus, in the present studies, a total of 20 µg of supercoiled DNA was routinely used in the cell transfection.

To study the effect of dexamethasone with isoproterenol and ß-adrenergic receptor antagonists or Rp-cAMP on the expression of pOCAT (ANG N-1498/+18), cells were incubated in DMEM without FBS, and various concentrations of hormones or drugs were added on day 1 after DNA transfection. The cells were harvested on day 3 for CAT assays.3 The plasmids pOCAT and pRSVCAT were used as negative and positive controls, respectively.

We have previously demonstrated that there is a dose-dependent relationship between dexamethasone concentration and the stimulation of expression of pOCAT (ANG N-1498/+18).3 Dexamethasone at 10-6 mol/L consistently produced a 1.5- to twofold stimulation of expression of pOCAT (ANG N-1498/+18). Thus, we routinely used dexamethasone (10-6 mol/L) for the present studies.

To normalize the efficiency of transfection of various plasmids, 2 mg of pTKGH (a vector with the thymidine kinase enhancer/promoter fused to the 5' human growth hormone gene) was cotransfected with pOCAT (ANG N-1498/+18). The presence of human growth hormone (National Institute of Arthritis, Metabolism, and Digestive Diseases–human growth hormone-I-1, AFP-4793B) or insulin growth factor-I (IGF-I, Sigma Chemical Co) at levels up to 4.5x10-9 mol/L and 12.8x10-9 mol/L, respectively, had no stimulatory effect on the expression of pOCAT (ANG N-1498/+18) in Hepa 1-6 cells (M. Ming, unpublished observations, 1994). Similarly, the presence of isoproterenol (10-5 mol/L), propranolol (10-5 mol/L), atenolol (10-5 mol/L), ICI 118,551 (10-5 mol/L), or dexamethasone (10-6 mol/L), or a combination of both dexamethasone (10-6 mol/L) and isoproterenol (10-5 mol/L), had no stimulatory effect on pTKGH expression (M. Ming, unpublished results, 1994). However, the results presented here were normalized to the efficiency of transfection of pTKGH in the absence of various hormones or drugs added. The radioimmunoassay for human growth hormone was performed according to the method described previously.17 18 The level of transfection efficiency for pOCAT (ANG N-1498/+18) ranged from 25% to 35% compared with pRSVCAT.

Chloramphenicol Acetyltransferase Assay
The method for the CAT assay has been described previously.3 The results of all CAT assays are given as a mean±SD of triplicates.

Statistical Analysis
The experiments were run three times in triplicate. Values are given as mean±SD (n=3), and statistical analysis was done with Student's t test. A level of P<=.05 was regarded as significant.


*    Results
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 *Results
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Effect of Isoproterenol and Dexamethasone on the Expression of the pOCAT (ANG N-1498/+18) Fusion Gene in Hepa 1-6 Cells
Fig 1 shows that addition of isoproterenol (10-9 to 10-5 mol/L) enhanced the stimulatory effect of dexamethasone (10-6 mol/L) on the expression of pOCAT (ANG N-1498/+18) in a dose-dependent manner. The maximal (280%) and half-maximal (220%) enhancing effect appeared to be 10-5 mol/L and 10-7 mol/L, respectively. On the other hand, isoproterenol alone had no effect on the expression of pOCAT (ANG N-1498/+18), whereas the addition of dexamethasone (10-6 mol/L) alone stimulated the expression of pOCAT (ANG N-1498/+18) by 1.8-fold (P<=.05). These data suggest that isoproterenol and dexamethasone acted synergistically to stimulate the expression of pOCAT (ANG N-1498/+18).



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  		Figure 1. Bar graph shows the effect of isoproterenol (Isop; 10-9 to 10-5 mol/L) alone or combined with dexamethasone (DEX; 10-6 mol/L) on the expression of pOCAT (ANG N-1498/+18) in mouse hepatome (Hepa 1-6) cells. The chloramphenicol acetyltransferase (CAT) activity of the pOCAT (ANG N-1498/+18) in the absence of both dexamethasone and isoproterenol is expressed as 100% (control). Each point represents the mean±SD of a minimum of three determinations, and the probability values are derived from Student's t test (*P<=.05, **P<=.01, and ***P<=.005).

Effect of Rp-cAMP on the Expression of pOCAT (ANG N-1498/+18) in Hepa 1-6 Cells
Fig 2 shows that addition of Rp-cAMP (an inhibitor of cAMP-dependent protein kinase A I and II) inhibits the enhancing effect of isoproterenol (10-5 mol/L) on the expression of pOCAT (ANG N-1498/+18) in Hepa 1-6 cells in the presence of dexamethasone (10-6 mol/L). Maximal inhibition was found with 10-5 mol/L Rp-cAMP (P<=.01). Rp-cAMP (10-6 mol/L) also produced a significant inhibitory effect (P<=.05). These results indicate that the effect of isoproterenol was mediated via the cAMP-dependent protein kinase pathways.



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  		Figure 2. Bar graph shows the inhibitory effect of Rp-cAMP on the expression of pOCAT (ANG N-1498/+18) in mouse hepatoma (Hepa 1-6) cells stimulated by isoproterenol (Isop) and dexamethasone (DEX). Cells were incubated for up to 24 hours in the presence of dexamethasone (10-6 mol/L), isoproterenol (10-5 mol/L), and various concentrations of Rp-cAMP (10-11 to 10-5 mol/L). The chloramphenicol acetyltransferase (CAT) activity of the fusion gene in the absence of dexamethasone, isoproterenol, and Rp-cAMP is expressed as 100% (control). Each point represents the mean±SD of a minimum of three determinations (*P<=.05, **P<=.01, and ***P<=.005).

Effect of ß-Adrenergic Receptor Antagonists on the Expression of pOCAT (ANG N-1498/+18) in Hepa 1-6 Cells
Fig 3 shows that addition of propranolol (a ß1- and ß2-adrenergic receptor blocker; 10-5 mol/L) blocked the enhancing effect of isoproterenol on the expression of pOCAT (ANG N-1498/+18) in the presence of dexamethasone (10-6 mol/L) (P<=.01). It appears that lower concentrations of propranolol (less than 10-5 mol/L) did not exhibit an inhibitory effect.



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  		Figure 3. Bar graph shows the inhibitory effect of propranolol on the expression of pOCAT (ANG N-1498/+18) in the presence of dexamethasone (DEX) and isoproterenol (Isop) in mouse hepatoma (Hepa 1-6) cells. Cells were incubated for up to 24 hours in the presence of dexamethasone (10-6 mol/L), isoproterenol (10-5 mol/L), and various concentrations of propranolol (10-9 to 10-5 mol/L). The chloramphenicol acetyltransferase (CAT) activity of the fusion gene in the absence of dexamethasone, isoproterenol, and propranolol is expressed as 100% (control). Each point represents the mean±SD of a minimum of three determinations (*P<=.05, **P<=.01, and ***P<=.005).

Similarly, Fig 4 illustrates that the addition of ß2-adrenergic receptor antagonist (ICI 118,551) blocked the enhancing effect of isoproterenol in a dose-dependent manner. The maximal and half-maximal effects were 10-5 mol/L and 10-7 mol/L, respectively. On the other hand, atenolol (a ß1-adrenergic receptor antagonist) had no inhibitory effect on the expression of pOCAT (ANG N-1498/+18) at a dose as high as 10-5 mol/L (Fig 5). These results show that the enhancing effect of isoproterenol was mediated predominantly by the ß2-adrenergic receptors.



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  		Figure 4. Bar graph shows the inhibitory effect of ICI 118,551 on the expression of pOCAT (ANG N-1498/+18) in the presence of dexamethasone (DEX) and isoproterenol (Isop) in mouse hepatoma (Hepa 1-6) cells. Cells were incubated for up to 24 hours in the presence of dexamethasone (10-6 mol/L), isoproterenol (10-5 mol/L), and various concentrations of ICI 118,551 (10-9 to 10-5 mol/L). The chloramphenicol acetyltransferase (CAT) activity of the fusion gene in the absence of dexamethasone, isoproterenol, and ICI 118,551 is expressed as 100% (control). Each point represents the mean±SD of a minimum of three determinations (*P<=.05, **P<=.01, and ***P<=.005).



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  		Figure 5. Bar graph shows the effect of atenolol (10-9 to 10-5 mol/L) on the expression of pOCAT (ANG N-1498/+18) in the presence of dexamethasone (DEX; 10-6 mol/L) and isoproterenol (Isop; 10-5 mol/L) in mouse hepatoma (Hepa 1-6) cells. The chloramphenicol acetyltransferase (CAT) activity of pOCAT (ANG N-1498/+18) in the absence of dexamethasone, isoproterenol, and atenolol is expressed as 100% (control). Each point represents the mean±SD of a minimum of three determinations (*P<=.05, **P<=.01, and ***P<=.005).


*    Discussion
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 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
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ß-Adrenergic receptors are among the best-studied receptors.19 ß-Adrenergic receptors were initially subdivided into two categories, ß-1 and ß-2, on the basis of the rank order of potency of agonists. Recent studies using recombinant DNA technology, however, have cloned three different ß-adrenergic receptors.20 21 22 23 Thus, it is now generally accepted that there are three types of ß-adrenergic receptors.

Isoproterenol is known to stimulate the synthesis of hepatic intracellular cAMP via ß-adrenergic receptors.9 10 11 12 24 25 Our present studies (Fig 1) showed that addition of isoproterenol enhances the stimulatory effect of dexamethasone on the expression of the pOCAT (ANG N-1498/+18) in Hepa 1-6 cells. Thus, these studies are in agreement with our previous studies,3 which showed that 8-Br-cAMP enhances the stimulatory effect of dexamethasone on the expression of the ANG gene. The present studies indicate that the effect of isoproterenol may be via the cAMP-dependent protein kinase pathway. Indeed, our studies showed that addition of Rp-cAMP (an inhibitor of cAMP-dependent protein kinase A I and II14 ) inhibits the enhancing effect of isoproterenol (Fig 2). The present studies demonstrated that the effect of isoproterenol is mediated via the cAMP-dependent protein kinase pathway. Moreover, Fig 1 shows that the maximum enhancing effect of isoproterenol (10-5 mol/L) on the stimulatory effect of dexamethasone (10-6 mol/L) is no more than 1.5-fold compared with that of controls (in the presence of dexamethasone, P<=.05). These observations are also in agreement with studies of Ohtani et al26 and Ben-Ari et al,27 who showed that cAMP enhances the effect of dexamethasone on ANG secretion by primary hepatocyte cultures and on the accumulation of the ANG mRNA transcripts in rat hepatoma cells by about 1.5- to twofold over that of controls, respectively.

It has been shown that ß1-, ß2-, and ß3-subtype adrenergic receptors are present in the liver and hepatoma cells.13 24 28 29 Our present study showed that addition of propranolol or ICI 118,551 inhibits the enhancing effect of isoproterenol on the expression of pOCAT (ANG N-1498/+18) by dexamethasone, but the addition of atenolol has no inhibitory effect (Figs 3 through 5). These studies demonstrated that the enhancing effect of isoproterenol is mediated by the ß2-adrenergic receptors and not the ß1-adrenergic receptors. This is in agreement with the studies of Schmelck and Hanoune24 and Graziano et al28 showing that ß2-adrenergic receptors are predominant in the liver. Atenolol (10-5 mol/L) did not inhibit the enhancing effect of isoproterenol (Fig 5). A higher dose of atenolol (10-4 mol/L), however, was effective in inhibiting the enhancing effect of isoproterenol (M. Ming, unpublished results, 1993). Hence, it is possible that ß1-adrenergic receptors are also present in Hepa 1-6 cells but in a lesser amount than ß2-adrenergic receptors. Indeed, more experiments are definitely required to demonstrate the presence or absence of ß1-adrenergic receptors in mouse Hepa 1-6 cells.

Finally, an increased activation of the sympathetic nervous system30 31 and of the renin-angiotensin axis32 33 is believed to be involved in the pathogenesis of hypertension. Numerous studies have shown that Ang II enhances those responses (release of norepinephrine) that are elicited by postganglionic sympathetic nerve stimulation in vivo and in vitro.34 35 36 The recent studies of Matsukawa et al37 showed that administration of captopril (an angiotensin-converting enzyme inhibitor) significantly decreases the muscle sympathetic nerve activity in accelerated hypertensive compared with normotensive patients, suggesting that levels of plasma norepinephrine, which may reflect sympathetic nerve activity in the hypertensive patients, could depend on the concentration of Ang II (ie, activation of the renin-angiotensin system). On the other hand, there are only a few studies demonstrating that catecholamines have an effect on the release of Ang II.38 39 40 41 42 Nakamaru et al38 demonstrated that isoproterenol (10-9 to 10-6 mol/L) causes an increase in the release of Ang II from isolated perfused mesenteric arteries. The increase in Ang II release during isoproterenol infusion was blocked by propranolol. Captopril (2x10-6 mol/L) also inhibited the increase in Ang II induced by isoproterenol. Studies by Richards et al39 also showed that a high dose of isoproterenol (100 mmol/L) significantly stimulates the release of Ang II from neuronal cultures. Recent studies by Tang et al40 demonstrated that isoproterenol (10-7 to 10-5 mol/L) increases secretion of angiotensins from cultured bovine aortic endothelial cells in a dose-dependent manner. The addition of ICI 118,551 (10-6 mol/L) blocked the effect of isoproterenol but not atenolol (10-6 mol/L). More recent studies by Taddei et al41 42 demonstrated that infusion of isoproterenol into the brachial artery of hypertensive subjects stimulates a local outflow of Ang II.

All of these studies demonstrate that release of locally generated Ang II by isoproterenol is mediated by ß-adrenergic receptors. Unfortunately, there are no reports demonstrating that isoproterenol has an effect on the expression of hepatic and/or extrahepatic ANG gene. Our present study showed that high concentrations of isoproterenol enhance the stimulatory effect of dexamethasone on the expression of the ANG gene in Hepa 1-6 cells (Fig 1). This suggests that the sympathetic nervous system may have a regulatory role in the activation of the renin-angiotensin axis (ie, synthesis and release of Ang II). Hence, we speculate that the activation of the sympathetic nervous system during stress may enhance the effect of cortisol on the expression of the ANG gene in patients with Cushing's syndrome, since hypertension is present in 75% to 80% of those patients with hypercortisolism.43 44 More experiments are definitely required to confirm this hypothesis.

In summary, we have demonstrated that the addition of isoproterenol enhances the effect of dexamethasone on the expression of the ANG gene in Hepa 1-6 cells. The enhancing effect of isoproterenol is mediated via the ß2-adrenergic receptors and cAMP-dependent protein kinase pathway. Our data may be useful for a better understanding of the molecular mechanism(s) of glucocorticoid/catecholamine(s)-induced hypertension.


*    Acknowledgments
 
This work was supported by MRC grants MT-12569 and MT-11568 and in part by a grant from the Heart Stroke Foundation of Canada, "Fonds de la recherche en santé du Québec" (FRSQ), and Maisonneuve-Rosemont Hospital Research Center. We would like to thank Ilona Schmidt for her expert secretarial assistance and Dr Kenneth D. Roberts for his advice and comments. We would also like to thank the National Institute of Diabetes and Digestive and Kidney Diseases and National Hormone and Pituitary Program, University of Maryland, School of Medicine (Drs Salvatore Raiti and Albert Parlow) for the gift of the human growth hormone–radioimmunoassay kit (award 31730).


*    Footnotes
 
Reprint requests to John S.D. Chan, University of Montreal, Maisonneuve-Rosemont Hospital Research Center, 5415 Blvd de l'Assomption, Montreal, Quebec, Canada H1T 2M4.

Received October 5, 1993; first decision November 8, 1993; accepted October 3, 1994.


*    References
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 up arrowIntroduction
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 up arrowResults
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 *References
 

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