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Factors Derived from Adrenals Are Required for Activation of Cardiac Gene Expression in Angiotensin II-Induced Hypertension

Departments of Pharmacology and Toxicology, Physiology (O.V.), and Forensic Medicine (P.H.), Biocenter Oulu, University of Oulu, 90014 Oulu, Finland; and First Department of Internal Medicine, Semmelweis University (G.F., Z.L.-F., R.d., M.T.), 1083 Budapest, Hungary

Address all correspondence and requests for reprints to: Heikki Ruskoaho, M.D., Ph.D., Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, P.O. Box 5000, University of Oulu, 90014 Oulu, Finland. E-mail: heikki.ruskoaho{at}oulu.fi

	Abstract

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The mechanisms mediating the activation of cardiac gene expression during pressure overload are not fully understood. We examined whether angiotensin II-induced activation of ventricular gene expression is related to blood pressure and ventricular mass or requires other factors by infusing angiotensin II in sham-operated and adrenalectomized rats. In sham-operated rats, angiotensin II (33 µg/kg·h, sc) produced a significant increase in mean arterial pressure (measured by telemetry) within 3 h. Mean arterial pressure (up to 45 h) and the increase in left ventricular hypertrophy in adrenalectomized rats during angiotensin II infusion were similar to those in sham-operated rats. Angiotensin II produced 3.6-fold (P < 0.01) and 20.4-fold (P < 0.001) increases in ventricular atrial natriuretic peptide mRNA levels at 12 and 72 h, respectively. Angiotensin II infusion for 12 h also significantly increased the ventricular mRNA levels of B-type natriuretic peptide (5.2-fold) and adrenomedullin (1.4-fold). Adrenalectomy either abolished (atrial natriuretic peptide and adrenomedullin) or blunted (B-type natriuretic peptide) the early activation of ventricular gene expression by angiotensin II. The baseline synthesis of atrial natriuretic peptide, B-type natriuretic peptide, and adrenomedullin in the ventricle remained unchanged in adrenalectomized rats. In conclusion, our results indicate that factors derived from the adrenals are required for angiotensin II-induced early activation of cardiac gene expression.

	Introduction

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THE HEART ADAPTS to increased demands for hemodynamic load by increasing muscle mass through the initiation of a hypertrophic response (1). At the genetic level, cardiac overload is associated with rapid and transient induction of immediate-early genes that encode nuclear transcription factors (2). B-Type natriuretic peptide (BNP) and adrenomedullin (AM) are also expressed at this early stage (3, 4, 5). Subsequently, the genes for atrial natriuretic peptide (ANP), skeletal muscle -actin, and ß-myosin heavy chain are reinduced (1, 6, 7). In addition to mechanical load, a variety of neurohumoral factors have been implicated in initiating or mediating the reprogramming of gene expression in the hypertrophic heart. In particular, the renin-angiotensin system may play an important role in the adaptation of the heart to hemodynamic load (8). By using the cultured neonatal rat myocytes it has been reported that mechanical stretch is coupled with cellular release of angiotensin II (Ang II) and that it may act as a chemical mediator of stretch-induced myocyte hypertrophy (9). Increases in the ventricular expression of angiotensinogen, renin, angiotensin-converting enzyme, and type 1 Ang II receptor (AT₁) genes (8, 10, 11) have been demonstrated in response to pressure overload. Ang II up-regulates the gene expression of natriuretic peptides (5), and chronic antagonism of AT₁ receptor and angiotensin-converting enzyme inhibitors attenuate hypertrophic process and the synthesis of ANP, BNP, and AM during pressure overload (12, 13, 14). However, it has not been clearly identified whether hemodynamic, myocardial, or other effects mediate the up-regulation of cardiac gene expression by Ang II.

It has been reported that bilateral adrenalectomy (ADX) partially prevents the cardiac hypertrophy induced by aortic coarctation (15, 16, 17). In the present study we tested the hypothesis that the activation of cardiac gene expression by Ang II requires intact function of the adrenal glands. We measured ANP, BNP, and AM mRNA levels in the ventricles as well as tissue and plasma levels of ANP, BNP, and AM during the early course of the Ang II-induced hypertension in normal and adrenalectomized rats.

	Materials and Methods

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Experimental protocol
Male Sprague Dawley rats (n = 164; weighing 313 ± 3 g) were housed in an experimental animal laboratory with free access to drinking fluid and food pellets. A 0600 h on/1800 h off environmental light cycle was maintained. The rats were subjected to sham operation, bilateral ADX, Ang II (Sigma, St. Louis, MO) infusion or bilateral ADX plus Ang II infusion. Bilateral ADX was performed using a dorsolumbar approach, making separate incisions on each side. All rats, including Ang II-infused rats, were subjected to the same operation (skin incision) independently whether osmotic minipumps were implanted sc afterward or not. In sham-operated rats for adrenalectomy further muscle incisions were made at both sides of the vertebral column without removing the adrenal glands. The efficacy of ADX was verified by postmortem examination of the suprarenal region. In a separate series of experiments, rats were subjected to sham operation, spironolactone administration, Ang II infusion, and Ang II plus spironolactone. Ang II (33 µg/kg·h) was administered via osmotic minipumps (1003D, Alzet, Palo Alto, CA; pumping rate, 1 µl/h), which were implanted sc at the nape of the neck. Spironolactone (100 mg/kg) was injected sc 24 h before and at the start of vehicle and Ang II infusion by osmotic minipumps. On 12 or 72 h of treatment, animals were decapitated, and blood was collected from the abdominal aorta into chilled tubes containing heparin. The plasma was separated by centrifugation at 4 C and kept at -80 C until assayed. Hearts were removed, and chambers were separated from each other (18). Left ventricular tissue samples were blotted dry, weighed, immersed in liquid nitrogen, and stored at -80 C until assayed. The experimental design was approved by the Animal Use and Care Committee of the University of Oulu.

Blood pressure monitoring
In a separate series of experiments, the rats were anesthetized with 250 µg/kg medetomidine hydrochloride and 50 mg/kg ketamine hydrochloride, ip, and instrumented with a catheter in the abdominal aorta below the renal arteries coupled with a sensor and transmitter (TA11PA-C40, DataSciences, Minneapolis, MN) for telemetric monitoring of blood pressure. On the seventh day after implantation, the rats were subjected to sham operation, bilateral ADX, Ang II infusion, or bilateral ADX plus Ang II infusion, as described above. Blood pressure and heart rate were measured every 10 min and averaged every hour throughout the equilibration period and for 72 h during treatments.

Isolation and analysis of mRNA
Total RNA was isolated from left ventricles by the guanidine isothyocianate-CsCl method (3). For the RNA Northern blot analysis, 20-µg samples of the RNA were separated on agarose-formaldehyde gel electrophoresis and transferred to nylon membranes (Hybond-N, Amersham Pharmacia Biotech, Arlington Heights, IL). Full-length rat ANP cDNA probe (19), a 390-bp rat BNP cDNA probe (20), rat AM cDNA probe (nucleotides 287–736), and 18S cDNA probe (3) were labeled, and the membranes were hybridized and washed as described previously (18). The hybridization signals of ANP, BNP, and AM mRNA were normalized to that of 18S in each sample.

Hormone measurements
Immunoreactive ANP (ir-ANP), ir-N-terminal pro-ANP (ir-NT-pro-ANP), ir-BNP, and ir-AM levels were measured by RIAs from extracted plasma or left ventricular tissue samples as described previously (3, 4, 21). The sensitivities of the ANP, NT-pro-ANP, BNP, and AM assays were 1, 0.2, 2, and 1 fmol/tube, respectively. The intra- and interassay variations in each assay were less than 10% and 15%, respectively. Serial dilutions of the extracted samples showed parallelism with the standards. Tissue peptide levels are expressed as the concentration per mg wet wt.

Plasma catecholamines were purified by Al₂O₃ extraction, and norepinephrine and epinephrine were analyzed by HPLC with an electrochemical detector (22). Corticosterone was determined from unextracted plasma (diluted 1:200) using a commercial RIA kit (DRG Instruments, Marburg, Germany, catalog no. RIA-0210). Aldosterone was first extracted from 0.3-ml plasma samples with 3 ml ethyl acetate-hexane (3:2 dilution), and aldosterone was determined using a commercial RIA kit (DRG Instruments, catalog no. RIA-0206). Both assays were performed according to the manufacturer’s instructions.

Statistics
The results are expressed as the mean ± SEM. The data were analyzed by one-way ANOVA, followed by Bonferroni post-hoc test. The hemodynamic variables were analyzed with repeated measures ANOVA. The relationships between left ventricular hypertrophy and mRNA and peptide levels were determined using linear regression analysis. P < 0.05 was considered statistically significant.

	Results

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Hemodynamics and left ventricular weight (LVW) in Ang II-infused animals
Mean arterial pressure and heart rate, measured by telemetry, were similar in all groups before beginning the treatments (Fig. 1). In intact rats, Ang II significantly increased mean arterial pressure within 3 h, which persisted throughout the 72 h of infusion (F = 8.7; P < 0.05; Fig. 1A). The mean arterial pressure of adrenalectomized rats during Ang II infusion did not differ from that of sham-operated rats up to 45 h, but thereafter tended to be lower (at 72 h: Ang II plus ADX, 130 ± 4; Ang II, 167 ± 11 mm Hg; P = 0.3). The heart rate decreased significantly (F = 25.5; P < 0.001) within 5–10 h after starting Ang II infusion in sham-operated rats, and this decrease in heart rate was smaller in Ang II-infused adrenalectomized rats (F = 39.6; P < 0.001; Fig. 1B). ADX alone had no statistically significant effect on mean arterial pressure (F = 0.56; P = 0.5); however, it increased the heart rate (F = 22.4; P < 0.001; Fig. 1B). The index of left ventricular hypertrophy, LVW to body weight (BW) ratio, was significantly higher in Ang II-infused sham-operated, and adrenalectomized rats than in respective control groups at 72 h (Table 1). ADX did not significantly change BW, LVW, and LVW/BW ratios compared with sham-operated animals (Table 1). Thus, hemodynamic parameters (up to 45 h) and the degree of left ventricular hypertrophy in adrenalectomized rats during Ang II infusion were comparable to those in sham-operated rats.

View larger version (27K): [in this window] [in a new window]   Figure 1. Mean arterial pressure and heart rate in Ang II-infused intact and ADX rats. Ang II (33 µg/kg·h; arrow) was infused sc by using osmotic minipumps for 72 h. , Sham-operated animals (n = 6); •, ADX (n = 6); , Ang II (n = 6); , Ang II plus ADX (n = 8). Results are expressed as the mean ± SEM.

View larger version (87K): [in this window] [in a new window]   Figure 2. Northern blot analysis showing the effect of administration of Ang II for 12 and 72 h on left ventricular ANP mRNA, BNP mRNA, and AM mRNA levels in intact and ADX rats. These are representative autoradiographs in which 20 µg total RNA were electrophoresed on agarose-formaldehyde gel, transferred to nylon, and hybridized with 32P-labeled probes. Single 0.9-, 0.9-, and 1.6-kb mRNA species, respectively, were identified with rat ANP, BNP, and AM probes. Hybridization signals for 18S ribosomal RNA are also shown.

View larger version (27K): [in this window] [in a new window]   Figure 3. Effect of Ang II infusion on left ventricular ANP mRNA and ir-ANP levels in intact or ADX rats. mRNA results are expressed as the ratio of ANP mRNA to 18S, as determined by Northern blot analysis. Results for sham (n = 18 and 21), Adx (n = 28 and 22), Ang II (n = 9 and 9), and Ang II plus Adx (n = 11 and 15) animals at 12 and 72 h, respectively, are shown. Results are the mean ± SEM. **, P < 0.01 vs. sham; ***, P < 0.001 vs. sham; , P < 0.001 vs. Ang II; , P < 0.05 vs. ADX.

View larger version (26K): [in this window] [in a new window]   Figure 4. Effect of Ang II infusion on left ventricular BNP mRNA and ir-BNP levels in intact or ADX rats. mRNA results are expressed as ratio of BNP mRNA to 18S as determined by Northern blot analysis. Results are the mean ± SEM. **, P < 0.01 vs. sham; ***, P < 0.001 vs. sham; , P < 0.05 vs. Ang II; , P < 0.05 vs. ADX. For the number of experiments, see Fig. 3.

Ventricular AM mRNA and ir-AM and plasma AM levels
Ang II induced a transient 1.4-fold increase in AM mRNA and a 1.5-fold increase in ir-AM levels in the left ventricles at 12 h (Figs. 2 and 5). Plasma ir-AM levels were also increased by Ang II at 12 h and returned to control values at 72 h (Table 2). No significant correlation was found between left ventricular AM mRNA levels and LVW/BW ratio (r² = 0.04; n = 38; P = 0.6). ADX completely abolished the Ang II-induced increases in left ventricular AM mRNA levels (P < 0.001) and attenuated the increase in ir-AM in the left ventricles produced by Ang II (Fig. 5). Interestingly, although the adrenal glands were originally suggested to be a source of circulating AM (23), plasma ir-AM levels in adrenalectomized animals were higher than those in sham-operated animals (Table 2).

View larger version (32K): [in this window] [in a new window]   Figure 5. Effect of Ang II infusion on left ventricular AM mRNA and ir-AM levels in intact or ADX rats. mRNA results are expressed as the ratio of AM mRNA to 18S as determined by Northern blot analysis. Results are the mean ± SEM. *, P < 0.05 vs. sham; **, P < 0.01 vs. sham; , P < 0.001 vs. Ang II. For the number of experiments, see Fig. 3.

To test whether the effects of Ang II on cardiac gene expression are due to increased plasma aldosterone concentrations, we administered spironolactone, an aldosterone receptor antagonist, at a dose of 100 mg/kg in vehicle- and Ang II-treated animals. Previously, spironolactone at doses of 20–100 mg/kg, sc, have been shown to prevent myocardial fibrosis (24, 25). As shown in Fig. 6, spironolactone infusion did not significantly modulate the increase in ANP and BNP mRNA levels induced by Ang II infusion at 12 h. Furthermore, no significant differences in plasma Na⁺ or K⁺ concentrations were observed at 12 h after adrenalectomy, Ang II infusion, or combined adrenalectomy and Ang II treatment (data not shown), suggesting that these ions are not involved in producing early changes in cardiac gene expression.

View larger version (23K): [in this window] [in a new window]   Figure 6. Effect of Ang II infusion on left ventricular ANP mRNA and BNP mRNA levels in intact or spironolactone-treated rats at 12 h. mRNA results are expressed as ratios of ANP mRNA and BNP mRNA to 18S as determined by Northern blot analysis. There were six experiments in each group. Results are the mean ± SEM. **, P < 0.01; ***, P < 0.001 (vs. sham).

	Discussion

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Molecular events triggered by pressure overload include the activation a number of genes, such as cellular oncogenes (c-fos, c-myc, c-jun, and Egr-1) (2, 6), cardiac peptides (ANP, BNP, and AM) (4, 5, 6), and structural genes (6, 7). Expression of ANP, BNP, and AM genes is induced by myocyte hypertrophy in vitro (5, 26, 27) as well as by ventricular hypertrophy in vivo (2, 4, 14, 20, 28). In the present study ventricular ANP gene expression was up-regulated even before the changes in left ventricular mass occurred in response to Ang II infusion. This is the first report to show a rapid induction of ventricular ANP gene expression as early as within 12 h in Ang II-induced hypertension. In contrast to ANP, administration of Ang II resulted in transient induction of both BNP and AM gene expression. Previously, the induction of BNP gene expression has been shown to be one of the earliest cardiac myocyte-specific markers of hemodynamic overload (3, 18), and AM mRNA and peptide levels are increased within 2 h of pressure overload produced by vasopressin infusion in conscious rats (4). Although AM gene expression has been shown to be activated acutely after aortic banding, no induction was seen in the chronic phase of cardiac hypertrophy (14).

The key finding of the present study was the lack of up-regulation of ANP and AM gene expression in the left ventricle by pressure overload by Ang II in adrenalectomized rats despite similar blood pressure (up to 45 h) and hypertrophic process as in sham-operated controls. Removal of adrenal glands also abolished the correlation between ANP gene expression and left ventricular mass. These results indicate that the early phase of hypertrophic response of ANP and AM genes induced by Ang II requires factors originating from the adrenal glands. We also found that ADX blunted, but did not abolish, Ang II-induced increases in ventricular BNP gene expression and did not modulate the correlation between BNP mRNA levels and left ventricular mass. Thus, the early up-regulation of BNP gene expression by Ang II is less dependent on adrenal factors. In agreement with this, BNP production in aortic-banded hypertensive rats after 6 wk was more sensitive than ANP to the load-dependent component (12). Interestingly, ANP gene expression was most sensitive to the inhibition by ADX at the early phase of overload (12 h), suggesting that the actions of adrenal factors, pressure load, and hypertrophy on cardiac gene expression may vary during the distinct phases of Ang II-induced hypertension.

We measured circulating catecholamine and corticosteroid levels mainly to validate our experimental model. In adrenalectomized rats the levels of the adrenal-derived hormones aldosterone, corticosterone, and epinephrine were undetectable both under basal conditions as well as after the administration of Ang II. In sham-operated rats, Ang II infusion elevated the levels of aldosterone and epinephrine, but not those of corticosterone or norepinephrine. Aldosterone could be one of the adrenal-derived factors required for initiation of the genetic program associated with Ang II-induced left ventricular hypertophy. Long-term aldosterone treatment results in cardiac hypertrophy and fibrosis via both direct and hemodynamic mechanisms (29). Aldosterone enhances Ang II binding and potentiates the Ang II-induced hypertrophic response by stimulating cardiac AT₁ receptor gene expression and receptor density (30). Furthermore, in a chronic experimental model (31), mineralocorticoid receptor blockade has been shown to reduce angiotensin II-induced cardiac damage at 7 wk, and in patients with advanced heart failure, spironolactone treatment decreases mortality and morbidity (32). However, in the early phase of ventricular hypertrophy, aldosterone seems not to be the adrenal-derived factor required for the induction of cardiac gene expression, as spironolactone administration did not attenuate Ang II-induced early increase in ANP and BNP gene expression. On the other hand, glucocorticoids have been found to increase the synthesis and processing of pro-ANP in rat atrial and ventricular cardiomyocytes (33). Thus, a normal plasma glucocorticoid level might be required as a permissive factor for the normal production of cardiac peptide hormones, perhaps by preserving the function of the key signal transduction pathways. Finally, catecholamines are well known stimulators of cardiac gene expression and peptide secretion (5). Our present results, however, do not allow us to precisely define which factors are predominantly responsible for the inhibition of Ang II-induced activation of cardiac gene expression. The relative importance of the above-mentioned factors as well as identification of the roles of novel factors regulating Ang II action, such as AT₁ receptor-associated protein, represent logical targets for future study. AT₁ receptor-associated protein interacts with AT₁ receptor, and its overexpression inhibits the Ang II signaling cascade (34).

Previous studies are consistent with the hypothesis that AM, as a natriuretic and vasodilating peptide (23), may play a compensatory role in the maintenance of intravascular volume and cardiac filling pressures during increased cardiac workload, similarly to ANP and BNP (5, 35). The increased cardiac expression and synthesis of these peptides may constitute a local paracrine mechanism to offset cardiac dysfunction and support cardiac work during the pressure-induced hypertrophic process. In vitro, ANP (36, 37) and AM (27) have been reported to inhibit cardiomyocyte hypertrophy in an autocrine or paracrine manner. Complete disruption of A-type natriuretic peptide receptor (38) or ANP gene (39) results in marked cardiac hypertrophy in mice with a modest increase in blood pressure, whereas transgenic mice overexpressing ANP have a low heart weight (40). Masciotra et al. (41) have shown that low ventricular ANP gene expression is linked genetically to high cardiac mass independent of blood pressure. Our results agree with the latter study by showing a dissociation between the hypertrophic process and increased ANP, BNP, and AM gene expression.

In summary, Ang II-induced hypertension produced an early activation of left ventricular ANP, BNP, and AM gene expression. Our study for the first time shows that activation of ventricular gene expression of ANP and AM and perhaps BNP as well by Ang II has components independent from hemodynamic changes and left ventricular hypertrophy and requires factors derived from the adrenals. Furthermore, the importance of adrenal factors, pressure load, and hypertrophy on cardiac gene expression appears to vary during the distinct phases of Ang II-induced hypertension.

	Acknowledgments

 
We thank Marja Arbelius, Esa Kerttula, Tuula Lumijärvi, Ulla Pohjoisaho, and Sirpa Rutanen for their expert technical assistance.

	Footnotes

 
This work was supported by grants from the Academy of Finland, the Sigfrid Juselius Foundation, and the Finnish Foundation for Cardiovascular Research.

Abbreviations: ADX, Adrenalectomy, adrenalectomized; AM, adrenomedullin; Ang II, angiotensin II; ANP, atrial natriuretic peptide; AT₁, type 1 Ang II receptor; BNP, B-type natriuretic peptide; BW, body weight; ir-, immunoreactive; ir-NT, immunoreactive N-terminal; LVW, left ventricular weight.

Received March 6, 2001.

Accepted for publication June 11, 2001.

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				G. Foldes, S. Vajda, Z. Lako-Futo, B. Sarman, R. Skoumal, M. Ilves, R. deChatel, I. Karadi, M. Toth, H. Ruskoaho, et al. Distinct modulation of angiotensin II-induced early left ventricular hypertrophic gene programming by dietary fat type J. Lipid Res., June 1, 2006; 47(6): 1219 - 1226. [Abstract] [Full Text] [PDF]

				Z. Lako-Futo, I. Szokodi, B. Sarman, G. Foldes, H. Tokola, M. Ilves, H. Leskinen, O. Vuolteenaho, R. Skoumal, R. deChatel, et al. Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart Circulation, November 11, 2003; 108(19): 2414 - 2422. [Abstract] [Full Text] [PDF]

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