Published online before print April 25, 2005, doi: 10.1161/01.CIR.0000163562.82134.8E
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(Circulation. 2005;111:2157-2164.)
© 2005 American Heart Association, Inc.
Coronary Heart Disease |
Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction
From the Pfizer-KEIO Research Laboratory (J.K., T.M., H.S., A.O.) and Cardiopulmonary Division, Keio University School of Medicine (S.O., T.A., T.Y.), Tokyo, Japan.
Correspondence to Jun Katada, PhD, Research Park 2N4, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail katada{at}kt.rim.or.jp
Received July 2, 2004; revision received December 16, 2004; accepted December 21, 2004.
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Abstract |
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Background— The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)–dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II–independent remodeling is unclear.
Methods and Results— Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor–knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized.
Conclusions— Our results indicate that genetic blockade of AT1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II–independent mechanisms.
Key Words: myocardial infarction • remodeling • angiotensin
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Introduction |
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The renin-angiotensin-aldosterone system is closely involved in the pathogenesis of heart failure. Previous studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers reduce mortality and morbidity among patients with chronic heart failure (CHF) and left ventricular (LV) systolic dysfunction.1,2 However, cardiac dysfunction and cardiovascular deaths are still observed even when CHF patients are treated with ACE inhibitors or Ang II receptor blockers. The aldosterone escape phenomenon, ie, persistent production of aldosterone despite renin-angiotensin system blockade, may be responsible for the insufficient action of ACE inhibitors or Ang II receptor blockers in patients with CHF.
In the Randomized Aldactone Evaluation Study (RALES), treatment with the mineralocorticoid receptor antagonist spironolactone reduced overall mortality in patients with advanced heart failure.3 This finding was recently confirmed by The Eplerenone Postacute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) in postinfarction CHF patients with the use of a new selective mineralocorticoid receptor antagonist, eplerenone.4 It has also been reported that mineralocorticoid receptor antagonists prevent LV dysfunction and remodeling in several animal models of heart failure.5,6 Although one of the primary targets of aldosterone is the kidney, there is also evidence that aldosterone directly affects cardiac tissues and causes the development of cardiac hypertrophy, fibrosis, and heart failure.7,8
Accumulating evidence suggests production of aldosterone in cardiac tissues, particularly under pathological conditions. Aldosterone synthase (CYP11B2) is detected in the hearts of several species, including rats9,10 and humans.11,12 Cardiac aldosterone production has also been found in experiments demonstrating a gradient of plasma aldosterone concentrations between the anterior interventricular vein and coronary sinus in humans,13,14 and myocardial production of aldosterone has been demonstrated in the rat.15 Increased production of cardiac aldosterone under certain pathological conditions suggests that it could play an important role in the pathogenesis of cardiac diseases. However, there is little or no information on the regulation of cardiac synthesis of aldosterone apart from the finding of involvement of the local renin-angiotensin system.16
Harada et al17 demonstrated that Ang II type 1A receptor (AT1A) signals play a pivotal role in the progression of post–myocardial infarction (MI) LV remodeling, using genetically AT1A-deficient (knockout) (AT1A-KO) mice. However, it is notable that LV remodeling and cardiac dysfunction still occurred, even after AT1A-dependent signaling was eliminated completely. Hence, we hypothesized that Ang II–independent synthesis of cardiac aldosterone in post-MI hearts may be responsible for persistent LV remodeling. The aims of the present study were to determine whether Ang II–independent aldosterone synthesis is induced in the hearts of AT1A-KO mice after acute MI and to elucidate the pathophysiological roles of cardiac aldosterone synthesis in post-MI remodeling.
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Methods |
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Animals
Male 15-week-old AT1A-KO mice (n=40) were used in the study.18 Age-matched male mice with the same genetic background (wild-type [WT]) were used as controls (n=40). All experimental protocols conformed to international guidelines and were approved by the animal experimentation review board of Keio University School of Medicine.
Induction of MI
MI was induced with the coronary ligation technique, as described previously.17 Sham-operated mice were prepared in the same manner, but no coronary ligation was performed. Spironolactone (Sigma) was administered orally at 20 mg/kg per day for 28 days. Lisinopril was administered for 28 days by mixing with drinking water. The estimated dose of lisinopril was 20 mg/kg per day, which has been reported to prevent LV fibrosis in rats.19
Evaluation of Infarcted Hearts at Day 28
Echocardiography was performed in mice anesthetized with ketamine (70 mg/kg IP) and xylazine (4 mg/kg IP) with the use of an ultrasonograph (EnVisor, Philips Medical Systems Japan) equipped with a dynamically focused 9-MHz annular array transducer, as described previously.20 Hemodynamics were assessed with a 1.4F high-fidelity catheter (Millar Instruments Inc) inserted via the right carotid artery into the LV for recording LV systolic pressure, heart rate, and maximal rate of rise of LV pressure (dP/dTmax). Finally, the hearts were excised, and the LV with scar and the right ventricle (RV) were weighed separately. Evaluation of the infarct size, expressed as a percentage of the LV surface area, was conducted as described previously21 with the use of formalin-fixed longitudinal sections of LV. Hydroxyproline contents, a marker for the cardiac collagen protein level, were determined as described previously.22
Quantitative Reverse Transcription–Polymerase Chain Reaction
For quantitative reverse transcription–polymerase chain reaction (RT-PCR), total RNA, extracted from noninfarcted LV walls, was reverse transcribed to cDNA with oligo(dT)16 primers. PCR reactions were performed with the ABI PRISM 7700 Sequence Detector System (Applied Biosystems), which monitors the PCR reaction in real time. Oligonucleotide primers and TaqMan probes were designed from the GenBank databases with the use of Primer Express software (Applied Biosystems).23 Statistical analysis of the results was performed with the 
Ct value (Ctgene of interest–CtGAPDH). Relative gene expression was obtained by Ct methods (Ct sample–Ct calibrator), with WT sham mice used for comparison with the gene expression level of unknown samples.
Biochemical Analyses
Cardiac aldosterone was extracted from the hearts as described previously.15 Briefly, the excised hearts were washed thoroughly with ice-cold PBS to remove blood and then homogenized in 1 mL of methanol with the use of a Polytron homogenizer. After centrifugation at 3000g for 15 minutes, the supernatant was dried under vacuum (Savant Speed Vac SC-100 system) and then mixed with 1 mL PBS. Aldosterone concentrations were determined by radioimmunoassay system. Tissue aldosterone levels were expressed in pg/mg protein. Plasma aldosterone was directly determined by radioimmunoassay. Sodium and potassium concentrations in plasma samples, prepared from blood collected from the right carotid artery in chilled tubes containing 2 µL EDTA, were determined by flame photometry. Plasma concentrations of corticotropin were determined by radioimmunoassay.24
Statistical Analysis
All data are expressed as mean±SEM. Multiple comparisons were performed by 1-way ANOVA with Bonferroni correction. A probability value <0.05 was considered statistically significant.
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Results |
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Mortality Rate After Induction of MI
Eight of 40 WT MI mice died during the 28-day observation period (mortality rate, 20%). The mortality rate by day 28 was significantly lower in WT MI mice treated with spironolactone (7.5%) and in AT1A-KO MI mice (10%) than in untreated WT MI mice. All spironolactone-treated AT1A-KO MI mice and sham-operated mice survived throughout the experiment.
Body Weight, Infarct Size, and Tissue Weight
The percent infarct area was not statistically different among the 4 MI groups (vehicle-treated WT: 37±0.9%; vehicle-treated AT1A-KO: 37±0.9%; spironolactone-treated WT: 36±0.9%; spironolactone-treated AT1A-KO: 37±0.9%). There was no significant difference in body weight on day 28 among the 8 experimental groups (Table). The LV and RV weights of WT MI mice on day 28 were significantly higher than those of WT sham-operated mice (77% and 137% increase for LV and RV, respectively). LV and RV weights of AT1A-KO MI mice were lower than those of WT MI mice but still significantly higher than those of sham-operated AT1A-KO mice. LV and RV weights were further decreased by administration of spironolactone, and consequently these weights in spironolactone-treated AT1A-KO MI mice were comparable to those of sham-operated mice. Changes in lung weight showed similar trends.
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Echocardiographic Study
As shown in Figure 1A, LV posterior wall thickness was increased by 67.6% in WT MI mice compared with WT sham-operated mice. LV posterior wall thickness was also thicker in AT1A-KO mice, but a smaller increase in thickness occurred compared with that in AT1A-KO sham-operated mice. When given to AT1A-KO mice, spironolactone induced a further reduction in LV posterior wall thickness and almost normalized the wall thickness after MI. Similarly, LV end-diastolic internal diameter and LV systolic internal diameter were higher in WT MI mice than WT sham-operated mice (47% and 149% increase, respectively). Both changes were attenuated in AT1A-KO MI mice (Figure 1B and 1C), although both diameters were still larger than those of AT1A-KO sham-operated mice. In spironolactone-treated AT1A-KO MI mice, further inhibition of LV dimensions was observed. Consequently, percent fractional shortening value was significantly higher in spironolactone-treated AT1A-KO MI mice than in vehicle-treated AT1A-KO MI mice (Figure 1D).
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Spironolactone Improves Impaired Cardiac Function
As shown in Figure 2A, LV systolic pressure was decreased by 27.3% in WT MI mice (92.2±3.0 mm Hg in WT sham mice versus 67.0±2.4 mm Hg in WT MI mice; P<0.01). The decrease in LV systolic pressure was much smaller in AT1A-KO mice (10.3% decrease compared with sham AT1A-KO mice). Administration of spironolactone to AT1A-KO MI mice induced further attenuation of the LV systolic pressure decline, which became close to normal levels. Similar changes were noted in dP/dT (Figure 2B). A large reduction of dP/dT was observed in WT MI mice (45% reduction compared with WT sham mice; P<0.001). In contrast, dP/dT decrease was significantly attenuated in AT1A-KO MI mice. Spironolactone reversed the decrease in dP/dT observed in AT1A-KO MI mice. The heart rate was not statistically different among the 8 experimental groups (Figure 2C).
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Gene Expression and Collagen Level in Noninfarcted LV
As shown in Figure 3A and 3B, the expression levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) mRNAs, which are markers of cardiac hypertrophy, were enhanced in WT MI mice compared with WT sham mice (ANP: 6.3±0.4-fold increase; BNP: 4.9±0.4-fold increase). Upregulation of mRNA expression of both ANP and BNP was also observed in AT1A-KO MI mice, but the expression levels were significantly lower than those in WT MI mice. Further inhibition of ANP and BNP mRNA expression was noted when AT1A-KO MI mice were treated with spironolactone, resulting in the expression levels being almost comparable to those of sham-operated mice. As shown in Figure 3C and 3D, the expression levels of type I and type III collagen genes were higher in WT MI mice than in WT sham mice (type I collagen: 16.3±0.7-fold increase; type III collagen: 14.4±0.7-fold increase). Upregulation of these genes was partially attenuated in AT1A-KO MI mice. Treatment of AT1A-KO MI mice with spironolactone further attenuated the expression levels. Hydroxyproline content in the LV wall, a marker for collagen proteins, exhibited a similar trend (Figure 3E).
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Cardiac Production of Aldosterone
Quantitative RT-PCR showed small but detectable levels of CYP11B2 mRNA in sham-operated hearts. As shown in Figure 4A, the CYP11B2 expression level was significantly higher in WT MI hearts than in sham-operated mice (5.4±0.6-fold increase; P<0.01). In AT1A-KO MI mice, CYP11B2 gene expression was lower than in WT MI mice but still was significantly higher than in sham-operated AT1A-KO mice. CYP11B2 gene expression in adrenal gland did not differ in WT and KO mice with or without MI (data not shown).
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The cardiac aldosterone level was elevated in MI mice (Figure 4B) (297±40.3 pg/mg protein in WT MI mice versus 68±5.6 pg/mg protein in WT sham mice; P<0.001). A significantly high aldosterone level was also observed in AT1A-KO MI mice compared with AT1A-KO sham-operated mice, but the increase was smaller than that in WT MI mice. Plasma aldosterone levels were 0.17±0.02 ng/mL in WT sham-operated mice, 0.25±0.02 ng/mL in WT MI mice (P<0.05 versus WT sham mice), 0.16±0.03 ng/mL in AT1A-KO sham-operated mice, and 0.18±0.02 ng/mL in AT1A-KO MI mice (nonsignificant versus AT1A-KO sham-operated mice).
Mechanism Underlying Renin-Angiotensin System–Independent Aldosterone Production
To examine the possible involvement of Ang II or other active products of the renin-angiotensin system, such as Ang1–7, in cardiac aldosterone synthesis through receptors other than AT1A, we examined the effects of lisinopril, an ACE inhibitor. As shown in Figure 5A, treatment with lisinopril (20 mg/kg per day) significantly attenuated LV hypertrophy observed in WT mice but did not further reduce LV weight in AT1A-KO MI mice. Other parameters, including RV weight and the gene expression level of type I collagen, showed similar trends (data not shown). Treatment with lisinopril decreased cardiac aldosterone levels in WT MI mice but not in AT1A-KO MI mice (Figure 5B).
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Plasma concentrations of sodium, potassium, and corticotropin on day 28 did not differ among the 8 experimental groups (data not shown). As shown in Figure 5C, gene expression of melanocortin receptor type 2 (MC2R), a corticotropin receptor, was significantly upregulated in the noninfarcted LV wall of AT1A-KO MI mice compared with sham-operated AT1A-KO mice.
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Discussion |
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The major findings of the present study are as follows: (1) AT1A-KO mice with MI had cardiac hypertrophy, cardiac dysfunction, and collagen gene expression, along with increased cardiac expression of the CYP11B2 gene and elevated cardiac aldosterone levels. (2) Spironolactone administration inhibited LV remodeling and resulted in almost normalized LV geometry, as well as reversing altered cardiac gene expressions (ANP, BNP, type I and type III collagens) in AT1A-KO MI mice. These results suggest that aldosterone is produced via an Ang II–independent mechanism in hearts with MI and that it promotes cardiac hypertrophy, fibrosis, and subsequent heart failure after MI.
Several regulators are known to stimulate aldosterone synthesis in the adrenal cortex, including Ang II, corticotropin, and plasma concentrations of Na+ and/or K+. Among these, Ang II is the primary physiological regulator because it is well known that blockade of the renin-angiotensin system by ACE inhibitors or Ang II receptor blockers often results in transiently decreased plasma aldosterone concentrations. However, it is also known that the plasma aldosterone concentration returns to a normal or supranormal level after long-term blockade of the renin-angiotensin system, ie, so-called aldosterone escape. The molecular mechanism of this Ang II–independent aldosterone synthesis in adrenal glands has not been clarified to date. In the present study we found that similar Ang II–independent aldosterone synthesis occurs in post-MI hearts. As shown in Figures 4 and 5
, cardiac aldosterone content and gene expression of cardiac CYP11B2 were significantly elevated after MI in the hearts of AT1A-KO mice and in WT mice treated with lisinopril compared with the hearts of sham-operated mice. These results suggest that Ang II–independent aldosterone synthesis is induced in post-MI hearts. We confirmed that the plasma aldosterone concentration and CYP11B2 gene expression in the adrenal gland were not changed at this time point (28 days after induction of MI). A previous report has also shown that the cardiac, and not the adrenal, steroidogenic system is activated in MI rats.9 These data are consistent with results from human clinical studies25,26 showing that plasma aldosterone concentrations were normal or decreased 1 month after the onset of renin-angiotensin system blockade and that the aldosterone escape phenomenon is generally induced only after long-term (several months or longer) treatment. Therefore, it is possible that different molecular mechanisms underlie the aldosterone escape phenomenon in adrenal glands and Ang II–independent aldosterone synthesis in post-MI hearts.
The factors responsible for Ang II–independent aldosterone synthesis are not clear. Our results suggest that a steroidogenic corticotropin receptor, MC2R, may be involved in cardiac Ang II–independent aldosterone synthesis because MC2R receptor expression was significantly upregulated in post-MI hearts in AT1A-KO mice (Figure 5C). MC2R-dependent signaling by corticotropin is known to upregulate a series of steroidogenic enzymes, including CYP11B2. Therefore, it is possible that increased expression of MC2R may be involved in the activation of cardiac aldosterone production via upregulation of steroidogenic enzymes, including CYP11B2, via a renin-angiotensin system–independent mechanism. On the other hand, this pathway does not seem to be activated in the adrenal cortex under our experimental conditions. We detected neither an increased plasma corticotropin concentration nor increased gene expression of MC2R and CYP11B2 in adrenal glands in AT1A-KO mice 28 days after MI. Another possibility for the mechanism underlying cardiac Ang II–independent aldosterone production is evident in our previous study,9 in which it was demonstrated that treatment of rat MI hearts with high-dose spironolactone (80 mg/kg) resulted in increased expression of cardiac CYP11B2 and increased aldosterone levels. Basically, similar results were obtained in the present study, although there are some minor discrepancies that are probably explained by species differences. These results suggest that aldosterone itself could regulate CYP11B2 expression by a feedback mechanism in post-MI hearts. Thus, our current hypothesis regarding Ang II–independent aldosterone synthesis in post-MI hearts is that an activated corticotropin-dependent signal induced by upregulation of the corticotropin receptor is closely involved in aldosterone production, in addition to increased expression of CYP11B2 elicited by aldosterone. Further studies need to be conducted to elucidate the molecular mechanism underlying the cardiac aldosterone escape phenomenon.
The next key question is whether cardiac aldosterone plays a significant role in post-MI cardiac hypertrophy or fibrosis. The critical roles of aldosterone in vascular damage, cardiac hypertrophy, LV remodeling, or heart failure after acute MI have been widely reported in clinical studies3,4,27 and in animal models of acute MI.5,8,28 Recent studies have shown that aldosterone directly induces vascular damage and baroreceptor dysfunction and prevents norepinephrine uptake by the myocardium.29–31 It is highly plausible that one of the primary targets of aldosterone responsible for post-MI remodeling is the cardiovascular tissue. Our results showed that cardiac aldosterone content was significantly higher in hearts of AT1A-KO mice than in hearts of AT1A-KO sham-operated mice, although concentrations of plasma aldosterone were not significantly different between AT1A-KO sham-operated mice and AT1A-KO MI mice. Similar results were obtained in lisinopril-treated MI and sham-operated mice. Importantly, the severity of LV remodeling seems to be closely associated with cardiac aldosterone levels rather than plasma levels, which did not differ between sham-operated mice and MI mice. Furthermore, our results also show that a relatively low dose (20 mg/kg per day) of spironolactone, which does not affect hemodynamics, can significantly attenuate LV remodeling. Recently, Cohn et al26 reported sustained reduction of the plasma aldosterone level after renin-angiotensin system blockade using valsartan, but such reduction was independent of the clinical outcome in CHF patients, suggesting the significance of the aldosterone level in the myocardium rather than the level in plasma. Taken together, these previous data and our present results suggest that locally produced aldosterone in post-MI hearts could play a primary role in the pathogenesis of LV remodeling in an autocrine or paracrine manner.
Recent studies have shown that aldosterone has a rapid nongenomic action on many types of cells, including renal epithelial cells and vascular smooth muscle cells.32 In cardiovascular tissues, it has been suggested that aldosterone may regulate vascular tone via a rapid nongenomic pathway.33,34 Furthermore, aldosterone has positive inotropic effects on the heart.35,36 Interestingly, spironolactone itself has similar inotropic effects on isolated working hearts.36 Although the involvement of these rapid actions in post-MI cardiac function is not clear, their partial involvement in the observed therapeutic effects should be considered because the chronic inotropic effect of spironolactone could facilitate preservation of cardiac function.
Mineralocorticoid receptor antagonist treatment in combination with renin-angiotensin system blockade has been reported to have beneficial effects for patients with severe CHF. Although aldosterone escape could explain the beneficial effect of the combination therapy, the precise molecular mechanism has not been elucidated. Our present findings may help to explain, at least in part, the basis for the beneficial effects of combination therapy. It is highly likely that cardiac aldosterone also plays a critical role in the pathogenesis of heart failure in humans, and clinical use of a mineralocorticoid receptor antagonist, in addition to renin-angiotensin system blockade, could be potentially beneficial as a result of inhibition of the action of cardiac aldosterone produced via an Ang II–independent pathway.
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Acknowledgments |
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This work was supported in part by a grant from Pfizer Inc (to Drs Katada, Saito, and Ohashi). We greatly appreciate Tanabe Seiyaku Co Ltd for kindly providing the experimental animals.
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