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(Hypertension. 2000;36:506.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade

Yi Xu; Alexander S. Clanachan; Bodh I. Jugdutt

From the Division of Cardiology, Department of Medicine, and the Cardiovascular Research Group, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.

	Abstract

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Abstract—We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT₂R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT₂R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP₃R) and protein kinase C (PKC) proteins. We assessed AT₂R, angiotensin II type 1 receptor (AT₁R), IP₃R, and PKC protein expression (Western blots) and AT₂R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (n=6) were exposed to no IR, no IR+PD (0.3 µmol/L), IR, and IR+PD. Compared with no IR and no IR+PD, IR decreased (P<0.05) functional recovery and AT₂R mRNA and protein, as well as AT₁R mRNA (not protein) and IP₃R and PKC proteins. Compared with IR, PD+IR improved LV functional recovery (P<0.05) and markedly increased AT₂R mRNA and protein (P<0.001). However, PD did not change AT₁R mRNA or protein. More importantly, PD+IR markedly increased IP₃R and PKC proteins. The downregulation of AT₂R mRNA and protein with IR and their upregulation with PD indicate that the effects of PD are AT₂R specific. The overall results suggest that the cardioprotective effect of acute PD treatment on LV functional recovery after IR in the isolated working rat heart is specifically due to AT₂R blockade and is associated with enhanced downstream IP₃R and PKC signaling.

Key Words: angiotensin II • mRNA • inositol • protein kinases • ischemia

	Introduction

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Angiotensin II (Ang II), a key effector peptide of the renin-angiotensin system (RAS), plays an important role in the control of blood pressure and blood volume. ¹ High Ang II concentrations, associated with upregulation of the RAS after ischemia/reperfusion (IR), myocardial infarction (MI), or heart failure,² appear to be cardiotoxic and promote injury. Although most cardiovascular effects of Ang II are normally considered to be mediated via Ang II type 1 receptors (AT₁Rs), recent evidence suggests that in the long term, Ang II type 2 receptors (AT₂Rs) inhibit growth, promote apoptosis, decrease cellular matrix, decrease blood pressure, dilate glomerular afferent arterioles, increase renal and vascular NO production, and decrease heart rate.³ Upregulation of AT₂Rs after chronic MI or in heart failure^{4 5 6} is thought to mediate ventricular remodeling. Chronic antagonistic interaction between AT₁R and AT₂R is thought to be important in vascular remodeling.³ During chronic AT₁R blockade, effects of increased Ang II (due to loss of negative feedback on the RAS⁷ ) may be mediated by AT₂R activation, thereby contributing to the cardioprotective effects.^{8 9} The postulated mechanism involves kinin, NO, and cGMP signaling.¹⁰ In the isolated Langendorff (nonworking) rat heart, AT₁R blockade (produced either acutely or by prior short-term pretreatment) was reported to improve recovery of left ventricular (LV) function after IR.¹¹ In the isolated working rat heart, acute AT₂R blockade with PD 123,319 (PD) produced dramatic improvement of LV function after IR¹² ; however, AT₁R/AT₂R status was not determined.

Recently, the inositol 1,4,5-trisphosphate (IP₃) type 2 receptor (IP₃R) was implicated in calcium regulation in myocytes,^{13 14} protein kinase C (PKC) was associated with AT₂R-mediated effects,¹⁵ and PKC was associated with cardioprotection involving NO.¹⁶ Thus, we hypothesized that the cardioprotective effect of the AT₂R blockade during IR in the isolated working rat heart is associated with an increase in AT₂R mRNA and protein expression as well as with an increase in IP₃R^{13 14} and PKC^{15 16} proteins but with no change in AT₁R expression.

The aim of the present study was to determine whether the PD-induced cardioprotective effect during IR is associated with the upregulation of AT₂R protein and mRNA as well as IP₃R and PKC proteins.

	Methods

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Isolated Working Rat Heart Preparation
As described previously,^{12 17} male Sprague-Dawley rats (250 to 300 g) were anesthetized (sodium pentobarbital, 50 mg/kg IP), and their hearts were rapidly excised and placed in ice-cold Krebs-Henseleit solution. The aorta was cannulated, and initial Langendorff perfusion (10 minutes) was performed. The pulmonary artery and left atrium were cannulated, and the hearts were switched to the working mode by clamping the aortic outflow line and opening the left atrial inflow line. The working hearts were perfused in a closed recirculating system at 37°C in contact with 95% O₂/5%CO₂. Atrial pacing (300 bpm) was applied during aerobic perfusion. The perfusate (100 mL) was a modified Krebs-Henseleit solution containing 2.5 mmol/L CaCl₂, 11 mmol/L glucose, 1.2 mmol/L palmitate prebound to 3% BSA (fraction V), 0.5 mmol/L lactate, and 100 mU/L insulin. Perfusions were made at constant hydrostatic left atrial preload (11.5 mm Hg) and afterload (80 mm Hg). Heart rate, aortic systolic and diastolic pressures, cardiac output, and aortic flow were measured. Coronary flow, LV minute work (in joules), and coronary vascular conductance (expressed as mL · min^-1 · mm Hg^-1) were calculated.

Experimental Protocol
Hearts were randomly assigned to 4 groups of 6 each: control 1 (no IR+no PD), control 2 (no IR+PD), IR (no PD), and IR+PD (0.3 µmol/L). Control hearts were perfused aerobically for 80 minutes in the absence or presence of PD (added after 30-minute aerobic baseline perfusion). Hearts in the IR groups were perfused aerobically in the working mode for 50 minutes and then subjected to 30 minutes of global no-flow ischemia (in the presence or absence of PD). Hearts were not paced during ischemia. After ischemia, the left atrial inflow was reestablished, and pacing was recommenced after 3 minutes of reperfusion. PD was added to the perfusate 5 minutes before the onset of ischemia and remained throughout the reperfusion period. At the end of the experiments, myocardial tissue samples were stored at -70°C and powdered in liquid nitrogen for analysis of the expression of AT₁R and AT₂R protein and mRNA^{18 19} as well as IP₃R and PKC proteins.

Western Blot Analysis
Aliquots of powdered tissue (10 mg) were sonicated in homogenization solution (2% SDS, 100 mmol/L dithiothreitol, and 60 mmol/L Tris, pH 6.8) at 4°C and boiled at 100°C. The boiled homogenate was subjected to electrophoresis on a 9% polyacrylamide gel in SDS followed by electrotransfer to nitrocellulose by use of the mini–cell blot electrophoretic transfer system (Bio-Rad) at 4°C. The nitrocellulose membranes were then blocked with PBS supplemented with 5% (wt/vol) skimmed milk powder and 0.05% (vol/vol) Tween 20 at room temperature. For AT₁R protein, the nitrocellulose membranes were incubated with affinity-purified rabbit anti-human AT₁R antibody (Santa Cruz Biotechnology Inc) at a dilution of 1:2000 for 2 hours at room temperature. The membranes were washed with PBS–Tween 20 (0.05%) 3 times, then incubated with goat anti-rabbit IgG antibody conjugated to peroxidase, and visualized by use of chemiluminescence detection (ECL Western blot kit, Amersham). The intensity of bands was quantified by scanning densitometry with the use of image analysis software (Sigma Chemical Co). The same procedure used for AT₁R was used for AT₂R proteins, except that incubation with goat anti-human AT₂R antibody (Santa Cruz Biotechnology Inc) at a dilution of 1:500 was followed by incubation with donkey anti-goat IgG (BioCan Scientific). The same procedure used for AT₁R was used for the detection of IP₃R and PKC proteins, except for an incubation with goat anti-human nPKC and IP₃ type 2 antibodies (Santa Cruz) at a dilution of 1:100, followed by incubation with donkey anti-goat IgG. Gel transfer efficiency and retention were confirmed with reversible ponceau staining and Coomassie blue staining, respectively. Immunoblots were performed in triplicate, and the results were averaged.

cDNA Probe Preparation
cDNA for AT_1aR and AT₂R were used to prepare probes for analysis of rat AT₁R and AT₂R mRNA. Human AT₂R and mouse AT_1aR cDNA were subcloned²⁰ into plasmid pcDNA3. The plasmid DNA was then digested with the use of 2 restriction enzymes that flanked the cDNA for the receptors. A 1.1-kb fragment corresponding to the coding region of the human AT₂R cDNA was isolated from the plasmid via a restriction enzyme digest with EcoRI (Boehringer-Mannheim). The plasmid containing mouse AT_1aR cDNA was restriction enzyme–digested with HindIII and BamHI (Boehringer-Mannheim), removing a 1.1-kb fragment corresponding to the coding region of the mouse AT_1aR cDNA. In both cases, the cDNA was gel-purified, and 25 ng of each was labeled with [³²P]CTP (Dupont) and used as a probe in Northern blot analysis.

Northern Blot Analysis
Total RNA was extracted from rat myocardium by use of the acid guanidinium–thiocyanate–phenol–chloroform extraction method with TRIzol reagent (GIBCO-BRL). Aliquots (20 µg) of total RNA were size-fractionated by electrophoresis on a 1.0% agarose/3% formaldehyde gel. These RNA samples were then transferred to Nytran membranes (Schleicher and Schuell Co). Probes were labeled with [-³²P]dCTP by using a random primer method. The labeled probes were separated from unincorporated nucleotides by using Sephadex G-50 spin columns. After ultraviolet cross-linking for 30 seconds, the membranes were prehybridized in the solution mixture containing 50% formamide, 5x SSC, 5x Denhardt’s solution, 0.1% SDS, 0.05 mol/L sodium phosphate buffer (pH 6.8), 0.1% sodium pyrophosphate, and 50 µg/mL sheared herring sperm DNA at 42°C for 3 hours. The membranes were then hybridized with a ³²P-labeled probe specific for AT_1aR and AT₂R in the same buffer for 18 to 24 hours at 42°C. Membranes were washed successively at room temperature in 2x SSC containing 0.1% SDS for 30 minutes twice and 1x SSC containing 0.1% SDS for 30 minutes and then at 55°C in 0.2x SSC containing 0.1% SDS for 45 minutes. Membranes were exposed at -80°C for 1 to 2 weeks on Kodak X-OMAT film (Eastman Kodak). Autoradiograms were quantified by scanning densitometry with the use of image analysis software (Sigma). GAPDH was used to normalize differences in loaded and transferred mRNA.

Statistics
Values shown are mean±SEM. Data were analyzed by ANOVA (with repeated measures followed by a Student t test with the Bonferroni correction for repeated comparisons) and linear regression analysis. Statistical significance was set at P<0.05.

	Results

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Effect of PD on Recovery of Function
In agreement with previous findings,¹² PD improved recovery of postischemic LV work compared with IR alone (Figure 1). Baseline values of LV work for IR+no PD, IR+PD, no IR+no PD, and no IR+PD groups were similar (1.04±0.02, 1.09±0.03, 1.02±0.01, and 1.01±0.01 J, respectively). In the no IR+no PD group, there was no change in LV work during continued aerobic perfusion to 80 minutes, and the addition of PD had no effect. In the IR group, recovery of LV work during reperfusion was significantly depressed to 51±9% of the baseline value (P<0.001), and PD significantly improved recovery to 85±4% (P<0.05 versus IR). With PD, LV work during reperfusion did not differ from baseline (P=NS).

View larger version (26K): [in this window] [in a new window]   Figure 1. Effect of AT2R antagonism on recovery of work. *P<0.05 vs IR. Right upper inset shows LV work during aerobic perfusion with no IR+no PD (control 1) and no IR+PD (control 2).

Coronary flow and cardiac output were similar in the 4 groups during baseline perfusion, were unchanged with no IR+PD, became depressed after IR, and improved during IR+PD.

However, coronary vascular conductance did not change with no IR+PD or IR+PD.

Effect of PD on AT₂R Protein and mRNA
AT₂R protein decreased 4-fold with IR and increased 3-fold with IR+PD compared with no IR±PD (Figure 2). AT₂R mRNA decreased 3-fold with IR and increased markedly (10-fold) with PD. Neither AT₂R protein nor mRNA changed with no IR+PD.

View larger version (36K): [in this window] [in a new window]   Figure 2. Effects of PD on AT2R protein and AT2R mRNA. Control refers to no IR+no PD (control 1). GAPDH was used to normalize the differences in loaded and transferred mRNA. *P<0.001 for IR+PD vs no IR±PD groups; P<0.001 for IR+PD vs IR+no PD; and P<0.001 for IR+no PD vs no IR±PD groups.

Effect of PD on AT₁R Protein and mRNA
AT₁R protein did not change with IR, IR+PD, or no IR+PD (Figure 3). AT₁R mRNA decreased by 50% with IR but did not change with IR+PD or no IR+PD.

View larger version (39K): [in this window] [in a new window]   Figure 3. Effects of PD on AT1R protein and AT1R mRNA. *P<0.05 for IR+no PD vs no IR±PD groups.

Effect of PD on IP₃R and PKC Proteins
IP₃R protein decreased 2-fold with IR and increased 4-fold with IR+PD (Figure 4). PKC protein decreased 2-fold with IR and increased 2-fold with IR+PD.

View larger version (30K): [in this window] [in a new window]   Figure 4. Effect of PD on IP3R protein and PKC protein. *P<0.001 for IR+PD vs no IR±PD groups; P0.01 for IR+PD vs IR+no PD; and P<0.05 for IR+no PD vs no IR±PD groups.

	Discussion

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Although the cardioprotective effect of acute AT₂R blockade with PD on recovery of LV mechanical function after IR in the isolated working rat heart has been previously reported, ¹² the status of AT₂Rs/AT₁Rs associated with this response remains unclear. The major new finding in the present study is that the cardioprotective effect is specifically due to AT₂R blockade. Thus, PD increased AT₂R protein and mRNA expression but did not change AT₁R protein or mRNA. A second new finding is that this upregulation of AT₂Rs was associated with marked increase in IP₃R and PKC proteins, suggesting that the cardioprotection associated with AT₂R upregulation might involve downstream IP₃R and PKC signaling.

In the present study, the downregulation of both AT₁R and AT₂R with acute IR is consistent with receptor activation in response to the release of Ang II, whereas the upregulation of AT₂R alone after PD+IR is consistent with the effect of a selective antagonist. The lack of changes in AT₁R mRNA and protein in control groups (no IR±PD) indicates that the effect on AT₂R mRNA and protein with IR+PD was not a nonspecific effect but was specifically due to PD-induced AT₂R blockade. The rapid increase in AT₂R mRNA followed by protein with IR+PD and the rapid downregulation of AT₂R mRNA and protein with IR is consistent with the pattern seen with other signal transduction pathways during ischemia, such as for ß-adrenoceptors²¹ and ß-adrenoceptor kinase.²² Importantly, IR decreased IP₃R and PKC proteins.

The signaling mechanisms for acute or chronic stimulation of AT₂R are not as well defined as for AT₁R.^{2 3} Useful insights into chronic signaling mechanisms were gained from studies using chronic pretreatment with AT₁R blockers before IR; chronic treatment in MI, hypertrophy, or heart failure; gene deletion in AT₂R knockout mice; and chronic AT₂R overexpression.^{2 3} However, such chronic manipulations may alter populations and the expression and interactions of receptors and cause adaptive alterations in several unrelated proteins. In the present study, we determined the acute effects of AT₂R blockade in isolated working adult rat hearts. Although we did not directly measure Ang II release after IR, corroborative evidence^{23 24} suggests that the receptors might be exposed to a local increase in Ang II during IR. Acting via AT₁R, Ang II increases IP₃ and calcium and induces coronary vasoconstriction and a positive inotropic effect.²⁵ AT₁R signaling involves tyrosine kinase–mediated phosphorylation of downstream kinases and substrates, calcium-dependent events mediated by phospholipase C, and inhibition of adenyl cyclase.^{21 26} Stimulation of phospholipase C leads to the generation of IP₃ and diacylglycerol as second messengers. Some steps in AT₂R signaling include activation of protein tyrosine phosphatase, inhibition of extracellular signal–regulated kinase, dephosphorylation of Bcl-2 protein, stimulation of ceramide production, and activation of the kinin/NO/cGMP system.³ The latter mechanism was proposed to contribute to benefits of high Ang II levels during AT₁R blockade,^{8 9} but whether high Ang II levels can induce cardioprotection via AT₂R activation in the absence of AT₁R blockade has not been established.

In the present study, the coincident increase in AT₂R, IP₃R, and PKC proteins during PD-induced cardioprotection suggests that enhanced expression of these proteins by PD+IR is functionally important. PKC signaling has been characterized during ischemic preconditioning²⁷ and ischemia,²⁸ and PKC activation mediates inotropic responses.²⁸ Ping et al¹⁶ established that cardioprotection induced by late preconditioning involves NO-induced activation of PKC and that the increase in PKC is not an epiphenomenon. PKC activation has also been implicated in cardioprotection induced by ethanol in guinea pig hearts²⁹ and hypoxia-induced early preconditioning in neonatal rat myocytes.³⁰ Our finding of increased PKC protein in association with PD-induced cardioprotection during IR, but not in association with the control groups or IR alone, supports the idea that PKC might be a commonly shared critical downstream effector of the cardioprotective response. We are unaware of other reports of IP₃R upregulation in IR or in MI, hypertrophy, and heart failure.

Although these findings suggest that the acute cardioprotective effect of AT₂R blockade involves IP₃R and PKC signaling (Figure 5), the precise mechanisms have not yet been established. This might involve NO-dependent signaling. NO has been implicated in the modulation of cardiac function.³¹ A mechanism that might have participated in the cardioprotective effect of AT₂R blockade involves inhibition of apoptosis. Thus, apoptosis is accelerated by AT₂R³² and contributes to LV dysfunction after acute IR,³³ whereas its inhibition limits the dysfunction.³⁴ Another intriguing mechanism is that during AT₂R blockade, increased Ang II levels might mediate AT₁R activation, the converse of the AT₂R activation paradigm during AT₁R blockade. This increased AT₁R activation could elicit positive inotropism²⁵ via an increase in IP₃ and PKC.^{21 26}

View larger version (25K): [in this window] [in a new window]   Figure 5. Effect of AT2R blockade on cardioprotection during IR. A, IR produces local RAS activation and release of Ang II, which activates AT1R and AT2R and causes downregulation of AT1R and AT2R as well as IP3R and PKC; downstream signaling via IP3R, PKC, and mediators results in partial recovery. B, With AT2R blockade by PD, AT2R downstream signaling is impaired, AT2R is markedly upregulated, and IP3R and PKC are also modestly upregulated, suggesting that AT2R signaling involves IP3R and PKC. Endogenous mediators that signal through IP3R and PKC are enhanced, resulting in cardioprotection. Thus, enhanced IP3R and PKC might prime the tissues to the mediators independent of Ang II. Alternatively, Ang II acting via AT1R (unchanged [] with IR+PD) might have participated in cardioprotection.

The present study has several limitations. First, the isolated heart does not provide insight into chronic effects. Second, it does not allow localization of the changes in proteins to regions or cell types. Third, we did not measure PKC activity. Nevertheless, the finding that acute AT₂R blockade can be cardioprotective during IR may have important implications for human cardiovascular diseases, such as hypertension, MI, and congestive heart failure. The main reasons are that (1) AT₂Rs are more prevalent in human than rat hearts,³⁵ (2) AT₂Rs are upregulated in those disease states,⁶ (3) most Ang II in human hearts comes from non–angiotensin-converting enzyme pathways, such as chymase,³⁶ so that AT₁R blockade with or without angiotensin-converting enzyme inhibition is being proposed for therapy, and (4) patients with the above conditions are prone to acute coronary syndromes and are likely to undergo reperfusion. Whether acute AT₂R blockade might be beneficial (or harmful) in vivo in the absence of AT₁R blockade requires detailed investigation.

In conclusion, the cardioprotective effect of acute AT₂R blockade in isolated adult rat hearts is associated with the upregulation of AT₂R mRNA and protein as well as with increased IP₃R and PKC proteins. The findings suggest that the cardioprotective effect is associated with IP₃R and PKC signaling.

	Acknowledgments

 
This study was supported in part by a grant from the Heart and Stroke Foundation of Canada, Ottawa, Ontario. We thank Catherine Graham for manuscript preparation.

	Footnotes

 
Reprint requests to Dr B.I. Jugdutt, 2C2.43 Walter Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R7.

Received October 11, 1999; first decision November 24, 1999; accepted March 21, 2000.

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