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CARDIOVASCULAR
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
Received January 6, 2004; accepted March 8, 2004.
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Abstract |
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1 adrenoceptor agonist phenylephrine, angiotensin II, and endothe-lin-1 are potent hypertrophic factors. There is evidence of potential cross talk between these agents, particularly in terms of endothelin-1 as playing a central role in mediating the actions of other hypertrophic factors. Using cultured rat neonatal ventricular myocytes, we assessed the potential cross talk between these factors and sought to examine the potential underlying mechanisms. Twenty-four-hour exposure to either agent produced significant hypertrophy as determined by cell size and molecular markers. Although the hypertrophic effects of phenylephrine and angiotensin II were expectedly prevented by 1 and AT1 receptor antagonists, respectively, these effects were also blocked by the ETA receptor antagonist BQ123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] but not by the ETB antagonist BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-
-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine). Both phenylephrine and angiotensin II significantly increased protein expression of both endothelin receptor subtypes. Both phenylephrine and angiotensin II produced significant activation of p38 as well as extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase, although this was unaffected by endothelin receptor blockade. Further studies revealed that the effects of phenylephrine and angiotensin II were mediated by stimulated endothelin-1 production occurring via two separate mechanisms: angiotensin II by increasing the levels of the endothelin-1 precursor prepro endothelin-1 and phenylephrine by upregulating endothelin-converting enzyme 1. Our results indicate that the endothelin-1 system plays an obligatory role in the hypertrophic response to both phenylephrine and angiotensin II in cultured myocytes through a mechanism independent of mitogenactivated protein kinase activation.
). For example, one such group of hypertrophic agonists, including the 1 adrenergic agonist phenylephrine (PE), angiotensin II (AngII), and endothelin-1 (ET-1), bind to specific Gq protein-coupled receptor to initiate the intracellular response (Dorn and Brown, 1999). In cultured cardiac myocytes, activation of G protein-coupled receptors by PE, AngII, and ET-1 not only induces cardiac hypertrophy (Simpson et al., 1982; Dzau, 1988; Shubeita et al., 1990) but also up-regulates the activity of mitogen-activated protein kinases (MAPKs) (Clerk and Sugden, 2000; Molkentin and Dorn, 2001), a superfamily composed of three overall branches of the serine/threonine kinases extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38.
Recent evidence suggests cross talk between AngII and ET-1 (Mulder et al., 1997). For example, AngII has been shown to stimulate the production of ET-1 in neonatal rat ventricular myocytes through a mechanism involving prepro ET-1 stimulation (Ito et al., 1993). The potential role of the ET-1 system in regulating hypertrophic responses to AngII is of importance in terms of understanding the mechanistic basis for hypertrophic responses and also in terms of designing therapeutic strategies aimed at limiting the hypertrophic phenotype. However, it is not known whether ET-1 plays an obligatory role in the hypertrophic responses to other factors and whether there is reciprocity in cross talk between these agents. Accordingly, the present study was designed to address these questions as well as the potential underlying mechanisms. ET-1 has also been shown to activate ETA or ETB receptors on cardiomyocytes to induce cellular hypertrophy (Ito et al., 1993; Cullen et al., 2001), but there is no evidence to date whether the expression of ETA and ETB can be regulated by PE or AngII. Accordingly, we also sought to determine whether PE or AngII can directly modulate ET receptors in cultured cardiomyocytes.
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Materials and Methods |
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). In brief, the ventricles were excised, washed, and cut into small pieces in 15 ml of Hanks' balanced salt solution (Invitrogen, Burlington, ON, Canada), and then digested in 60 ml of Hanks' balanced salt solution containing 800 U of collagenase (Worthington Biochemicals, Lakewood, NJ) per ventricle. The digestion was performed in a circulating water bath to keep the reaction temperature at 37°C. The digestion was terminated by adding the same volume of 20% fetal bovine serum. The cells were sorted by a cell strainer to remove undigested particles and then centrifuged at 600g for 5 min at 4°C. The cell pellet was resuspended in a plating medium containing 10% fetal bovine serum and 0.1 mM bromodeoxyuridine and was preplated in tissue culture flasks for two times of 20 min to reduce contaminating nonmyocytes, after which the cells were transferred into Primaria cell culture dishes (BD Biosciences Labware, Mississauga, ON, Canada) and cultured for 48 h. The medium was replaced with a serum-free maintenance medium and incubated for another 24 h before being used for study. Approximately 95% of cells prepared by this method demonstrated sarcomeric myosin heavy chain staining, indicating relatively low nonmyocyte contamination (Rajapurohitam et al., 2003).
Experimental Design. Myocytes were treated with either PE (10 µM), AngII (100 nM), or ET-1 (10 nM) for 24 h. For some experiments, the cells were first treated with the appropriate antagonist for 15 min before agonist addition. These included the 1 adrenoceptor antagonist prazosin (1µM), the AT1 antagonist [Sar1-Ile8]-angiotensin II (1 µM), the AT2 antagonist PD 123319 (1 µM), the ETA antagonist BQ123 (100 nM), and the ETB antagonist BQ788 (1 µM). In addition, the endothelin-converting enzyme-1 (ECE-1) inhibitor phosphoramidon (PPRD) (10 µM) was used in some studies and added using a protocol identical to the receptor antagonists. All agents used were from Sigma Diagnostics Canada (Oakville, ON, Canada).
Cell Area Measurement. The cells were plated at a density of 1 x 106 cells/6-cm dish to obtain individually plated cells. At the end of the treatment period, the cells were washed twice with PBS after which they were viewed using a Leica DMIL inverted microscope equipped with a Polaroid digital camera. Eight random photographs were taken from each sample and surface area from at least five cells from each photograph was determined in a blinded manner using Mocha software (SPSS Inc., Chicago, IL). Thus, surface area from at least 40 cells was averaged to obtain one "n" value.
RT-PCR and Real-Time PCR. Myocytes were plated at 6 x 106 cells/6-cm dish. After washing twice with PBS, RNA was isolated by adding 1 ml of TRIzol reagent (Invitrogen) to each dish. Then 5 µg of total RNA was applied for reverse transcription by Superscript II reverse transcriptase (Invitrogen). One microliter from the 20 µl of cDNA product was used for each PCR reaction. RT-PCR was performed using a Genius DNA Engine thermocycler (Mandel Scientific Inc., Guelph, ON, Canada) with Platinum TaqDNA polymerase (Invitrogen). Realtime PCR was performed with a DNA Engine Opticon Real-Time system (MJ Research, Watertown, MA) with SYBR Green JumpStart Taq ReadyMix kit (Sigma Diagnostics Canada) according to the manufacturer's instructions. The primers and the PCR programs used are listed in Tables 1 and 2, respectively.
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Western Blot Analysis. Cells were plated at a concentration of 6 x 106 cells/6-cm dish. After washing twice with PBS, the cells were scraped into 100 µl of lysis buffer (20 mM Tris, 150 mM NaCl, 1% Triton X-100, 10% glycerol, 2 mM EDTA, 2 mM EGTA, 50 mM NaF, 200 µM Na3VO4, 10 mM Na4P2O7, 40 mM 
-glycerophosphate, 10 µg/ml leupeptin, 1 µM pepstatin A, 1 mM phenylmethylsulfonyl fluoride, and 1 µM colyculin A). The lysate was transferred to 1.5-ml Eppendorf tubes, homogenized, and then centrifuged at 10,000g for 5 min at 4°C. The supernatant was transferred to a fresh tube, and the protein concentration was assayed by Bradford protein assay kit (Bio-Rad, Mississauga, ON, Canada). Protein (30 µg) was loaded in 10% SDS-polyacrylamide gel electrophoresis, and transferred to nylon membrane (Amersham Biosciences UK, Ltd., Little Chalfont, Buckinghamshire, UK). The membranes were blocked in 5% dry milk for 3 h, primary antibody for 2 h, secondary antibody for 1 h, and then detected by enhanced chemiluminescence reagent (Amersham Biosciences UK, Ltd.). ETA, ETB, and actin antibodies were from Chemicon International (Temecula, CA) and used at a 1:500 dilution except for actin, which was used at a dilution of 1:2000 dilution. Antibodies against pp44/42, ERK, pp38, p38, pJNK, and JNK were purchased from Cell Signaling Technology Inc. (Beverly, MA) and used at a 1:1000 dilution.
Enzyme Immunometric Assay. Myocytes were plated at 3 x 106 cells/3.5-cm dish. Big ET-1 and ET-1 protein levels in the culture media were measured using enzyme immunometric assay kits (Assay Design, Chicago, IL) according to the manufacturer's instructions. The cross-reactivity of rat big ET-1 antibody with either ET-1, ET-2, or ET-3 was <0.1%, whereas cross-reactivity of the ET-1 antibody with either ET-2 or ET-3 was 3.32 and <0.1%, respectively.
Statistical Analysis. All values in the figures and text are presented as mean ± S.E.M. Sample size per experiment is indicated in the results. Data were analyzed by one-way analysis of variance with P < 0.05 considered to represent significant differences between groups.
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Results |
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To further assess the nature of the hypertrophic phenotype in response to agonists, we determined the mRNA expression of two molecular hypertrophic markers, atrial natriuretic peptide (ANP) and myosin light chain-2 (MLC-2) by RT-PCR and real-time PCR (Fig. 2). Both PE and AngII significantly increased expression of these two markers, which was prevented by the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788.
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Effect of 1 Adrenoceptor and AngII Receptor Blockade on ET-1-Induced Cardiac Hypertrophy. Studies were carried out, as summarized in Table 3, to assess whether the hypertrophic effect of ET-1 can be modulated by blocking 1 or AngII receptors. However, neither the 1 adrenoceptor antagonist prazosin, the AT1 receptor antagonist [Sar1-Ile8]-angiotensin II, or the AT2 receptor antagonist PD 123319 had any effect on ET-1-induced cardiac hypertrophy. Furthermore, prazosin has no effect on AngII-induced hypertrophy, whereas neither of the AngII antagonists influenced PE-induced hypertrophy (Table 3).
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Effect of PE and AngII on ETA and ETB Receptor Protein Expression in Cardiac Myocytes. Figure 3 summarizes our results aimed at assessing whether ET receptor expression is affected by either PE or AngII. Both the ETA and the ETB receptor were significantly increased after 24-h treatment with either agent. We next wished to determine whether the up-regulation of ET receptors occurred via direct effects or secondary mechanisms, possibly via ET-1 up-regulation. Initial studies determined the effect of PPRD, which inhibits the ECE-1 that converts big ET-1 to ET-1. As shown in Fig. 3, PPRD, which had no effect of its own completely prevented the up-regulation of the ETA receptor by both PE (A) as well as AngII (B). In contrast, PPRD directly increased ETB expression on its own and has no effect on ETB upregulation produced by either PE (Fig. 3C) or AngII (Fig. 3D).
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Effect of PPRD on PE and AngII-Induced Hypertrophy. As shown in Fig. 4, the hypertrophic effect of both PE and AngII was completely prevented by PPRD, which on its own was without effect, thus suggesting that endogenous ET-1 mediates the hypertrophic effect of these two agents.
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Comparative Effects of PE and AngII on ECE-1 and ET-1 Expression. The ability of PPRD to prevent the upregulation of the ETA receptor by both PE and AngII prompted us to examine whether ECE-1 could be directly modified by either agent as a potential explanation for ETA up-regulation. As shown in Fig. 5, PE significantly increased ECE-1 expression 3-fold, whereas AngII was completely without effect. In contrast, however, AngII increased expression of prepro ET-1 directly, although prepro ET-1 expression was unaffected by PE. Moreover, the magnitude of prepro ET-1 up-regulation was virtually identical to the effect of PE on ECE-1.
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Together, the results suggest an ability of PE and AngII to stimulate ET-1 production via two distinct mechanisms. To demonstrate this directly, we next studied the relative ability of each agent to augment synthesis of big ET-1, the immediate ET-1 precursor, as well as ET-1 itself by determining the levels of these peptides in culture medium after agonist addition. As shown in Fig. 6, both PE and AngII significantly increased ET-1 production, whereas, in contrast, only AngII significantly increased the levels of big ET-1. The increased ET-1 production induced by PE was abolished by the 1 antagonist prazosin, whereas the increased ET-1 and big ET-1 production induced by AngII was inhibited by the AT1 blocker [Sar1-Ile8]-AngII and to a lesser degree by the AT2 antagonist PD 123319. The ability of both AngII receptor antagonists to exert inhibitory effects was surprising, although this may infer a role for multiple receptor subtypes in mediating the effect of AngII on the ET-1 system.
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Effect of Treatments on MAPK Activity. All three hypertrophic factors used in this study activate MAPK pathways in cardiac myocytes, and we therefore explored whether the prevention of cardiac hypertrophy by BQ123 is related to MAPK activity. As shown in Fig. 7, PE significantly increased MAPK activity as evidenced by increased phosphorylation of p44/42 (ERK), p38, and JNK, whereas AngII has little effect. Moreover, PE- and AngII-induced MAPK activation was unaffected by either the ETA receptor antagonist BQ123 or the ETB receptor antagonist BQ788.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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). ET-1 acts via two G protein-coupled receptors (ETA and ETB), although the ETA receptor represents 90% of endothelin receptors in cardiomyocytes (Fareh et al., 1996; Sakai et al., 1996). ET-1 has been implicated in the pathophysiology of myocardial infarction and congestive heart failure (Ezra et al., 1989; Stewart et al., 1991; Grover et al., 1993), the latter role likely attributable to its potent hypertrophic actions, thus potentially contributing to the myocardial remodeling process (Yorikane et al., 1993). ET-1 and ET receptor expression can be increased by numerous factors such as cytokines, hormones, autocoids, fluid sheer, as well as various other factors (Rubanyi and Polokoff, 1994). AngII has been shown to up-regulate prepro ET-1 mRNA level in cultured cardiac myocytes (Ito et al., 1993), potentially suggesting that stimulation of ET-1 synthesis mediates at least some of the effects of this hormone. To assess and expand this hypothesis, we studied the effect of two hypertrophic factors, AngII and the 1 adrenoceptor agonist PE, on cardiomyocyte hypertrophy and carried out an in-depth assessment to determine whether the ET system mediates these hypertrophic responses. Our data strongly suggest an important role for ET-1 and its receptors, but especially the ETA receptor in mediating the actions of both AngII and PE through a mechanism involving increased synthesis of ET-1. However, our study also reveals that the ability of these agents to increase ET-1 production occurs via different mechanisms.
A role for ET-1 mediating the hypertrophy produced by PE and AngII is borne out by various lines of evidence that can be summarized as follows. The increased cell area produced by both agents was completely blocked by the ETA receptor antagonist BQ123. We also attempted to document changes in molecular markers. PE and AngII not only increased the cell area but also the expression of both ANP and MLC-2 (Chien et al., 1991). Moreover, both ET receptor antagonists blocked the up-regulation of ANP and MLC-2 induced by PE and AngII. The ability of the ETB blocker BQ788 to inhibit both ANP and MLC up-regulation by PE and AngII, while leaving increased cell area produced by both agents unaffected was surprising but may reflect the complexity of the hypertrophic process and ET signaling. Indeed, ETB represents only 10% of the ET receptor in cardiomyocyte (Fareh et al., 1996), and it is possible that blocking of ETB is sufficient to inhibit the hypertrophic marker expression but not the overall hypertrophic effect.
The ability of PE and AngII to up-regulate expression of both cardiac ET receptors ETA and ETB further supports the notion that the ET system could potentially mediate the effects of these agents. To assess whether PE and AngII directly up-regulate these receptors or whether this reflects a secondary response via endogenous ET-1, we determined the effect of PPRD, an agent that inhibits the enzyme ECE-1 that catalyzes the conversion of big ET-1 to ET-1. PPRD blocked the up-regulation of the ETA receptor by both PE and AngII, whereas it had no effect on ETB up-regulation by these agents. Moreover, PPRD surprisingly directly up-regulated ETB expression in the absence of any other intervention. The studies with PPRD further support the concept of ETA receptor mediation of hypertrophic responses because the agent blocked the increased cell area produced by both PE and AngII.
Studies with PPRD further suggested that endogenous ET-1 mediates the hypertrophic response to both PE and AngII. We sought to explore this concept by direct measurements of ET-1 and components of the ET-1 synthesis pathways. Indeed, both PE and AngII increased release of ET-1 from cardiac cells, although subsequent analysis revealed that this occurs via different mechanisms. Accordingly, AngII, but not PE increased big ET-1 levels. Moreover, PE, but not AngII stimulated ECE-1 expression, as reported previously by others (Kaburagi et al., 1999), whereas conversely, only AngII increased prepro ET-1 expression. The integration of these findings into our working hypothesis is summarized below.
As summarized in Fig. 7, we also studied the potential cell signaling mechanisms in mediating the hypertrophic responses by concentrating on the MAPK family. MAPK, but particularly ERK1/2, is generally associated with cell growth and is strongly activated by ET-1, PE, and AngII (Clerk et al., 1994; Miyata and Haneda, 1994), although it should be noted that ERK1/2 inhibition has been shown not to reduce the hypertrophic phenotype in various experimental settings (Clerk et al., 1998; Ono et al., 2000). In addition, both JNK and p38 can also be activated by PE and AngII in cardiac myocytes, although these are more markedly activated by cytotoxic cellular stresses such as osmotic or oxidative stress (Bogoyevitch et al., 1995; Clerk et al., 1998). Our results showed that the early stimulation of all three components of the MAPK family by PE and AngII was unaffected by ET receptor blockade. Thus, ET receptor blockade inhibits the hypertrophic response but leaves the MAPK activation unaffected. This finding is not completely surprising because 10-min treatment would not be expected to be sufficient time for either PE or AngII to increase synthesis of the ET-1 peptide. Overall, this finding suggests, but does not necessarily prove, that the obligatory role of ET-1 in mediating the hypertrophic response to either PE or AngII can be dissociated from MAPK activation.
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Conclusion |
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) or cardiomyocyte-specific ETA knockout mice (Kedzierski et al., 2003) failed to demonstrate a pivotal role for this receptor against AngII-induced hypertrophy. We are unable at present to explain the divergent results but this may represent the type of experimental model. Moreover, as suggested by these authors, it is possible under chronic in vivo conditions other mechanisms are activated to compensate for ETA inhibition such as the up-regulation of other receptor subtypes. In view of the potential therapeutic relevance of this phenomenon further work is necessary to fully understand the importance of these findings particularly under in vivo conditions. Our hypothesis regarding the nature of this activation based on our systematic evaluation of the ET system in response to the two agonists in cultured myocytes is summarized in Fig. 8. According to this scheme, both PE and AngII increase the production of ET-1, although via separate mechanism: AngII by increasing expression of prepro ET-1 and PE by activating ECE-1, thus resulting in increased conversion of big ET-1 to ET-1 with the latter acting on the ETA receptor to produce the hypertrophic response. Hypertrophy is thus prevented by PPRD because this agent blocks the conversion of big ET-1 to ET-1. The ability of PPRD to up-regulate the ETB receptor was surprising but may suggest that endogenous ET-1 serves as an inhibitory regulator of this receptor, which is then reversed by ECE-1 inhibition, or it may reflect a direct stimulatory effect of PPRD on the ETB receptor.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: PE, phenylephrine; AngII, angiotensin II; ET-1, endothelin 1; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun NH2-terminal kinase; PD123319, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate; BQ123, cyclo(D-Asp-Pro-D-Val-Leu-D-Trp); BQ788, N-cis-2,6-dimethylpiperidinocarbonyl-L--methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine; ECE-1, endothelin-converting enzyme1; PPRD, phosphoramidon; PBS, phosphate-buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; PCR, polymerase chain reaction; ANP, atrial natriuretic peptide; MLC, myosin light chain.
Address correspondence to: Dr. Morris Karmazyn, Department of Physiology and Pharmacology, University of Western Ontario, Medical Sciences Building, London, Ontario N6A 5C1, Canada. E-mail: morris.karmazyn{at}fmd.uwo.ca
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References |
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Bogoyevitch MA, Ketterman AJ, and Sugden PH (1995) Cellular stresses differentially activate c-Jun N-terminal protein kinases and extracellular signal-regulated protein kinases in cultured ventricular myocytes. J Biol Chem 270: 29710-29717.
Chien KR, Knowlton KU, Zhu H, and Chien S (1991) Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J 5: 3037-3046.[Abstract]
Clerk A, Bogoyevitch MA, Anderson MB, and Sugden PH (1994) Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. J Biol Chem 269: 32848-32857.
Clerk A, Michael A, and Sugden PH (1998) Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G proteincoupled receptor agonists, endothelin-1 and phenylephrine: a role in cardiac myocyte hypertrophy? J Cell Biol 142: 523-535.
Clerk A and Sugden PH (2000) Small guanine nucleotide-binding proteins and myocardial hypertrophy. Circ Res 86: 1019-1023.
Cullen JP, Bell D, Kelso EJ, and McDermott BJ (2001) Use of A-192621 to provide evidence for involvement of endothelin ET(B)-receptors in endothelin-1-mediated cardiomyocyte hypertrophy. Eur J Pharmacol 417: 157-168.[CrossRef][Medline]
De Smet HR, Menadue MF, Oliver JR, and Phillips PA (2003) Endothelin ETA receptor antagonism does not attenuate angiotensin II-induced cardiac hypertrophy in vivo in rats. Clin Exp Pharmacol Physiol 30: 278-283.[Medline]
Dorn GW, 2nd and Brown JH (1999) Gq signaling in cardiac adaptation and mal-adaptation. Trends Cardiovasc Med 9: 26-34.[CrossRef][Medline]
Dzau VJ (1988) Cardiac renin-angiotensin system. Molecular and functional aspects. Am J Med 84: 22-27.[CrossRef][Medline]
Ezra D, Goldstein RE, Czaja JF, and Feuerstein GZ (1989) Lethal ischemia due to intracoronary endothelin in pigs. Am J Physiol 257: H339-H343.
Fareh J, Touyz RM, Schiffrin EL, and Thibault G (1996) Endothelin-1 and angiotensin II receptors in cells from rat hypertrophied heart. Receptor regulation and intracellular Ca2+ modulation. Circ Res 78: 302-311.
Gan XT, Chakrabarti S, and Karmazyn M (2003) Increased endothelin-1 and endothelin receptor expression in myocytes of ischemic and reperfused rat hearts and ventricular myocytes exposed to ischemic conditions and its inhibition by nitric oxide generation. Can J Physiol Pharmacol 81: 105-113.[CrossRef][Medline]
Grover GJ, Dzwonczyk S, and Parham CS (1993) The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc Res 27: 1613-1618.
Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F, and Hiroe M (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Investig 92: 398-403.
Kaburagi S, Hasegawa K, Morimoto T, Araki M, Sawamura T, Masaki T, and Sasayama S (1999) The role of endothelin-converting enzyme-1 in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes. Circulation 99: 292-298.
Kedzierski RM, Grayburn PA, Kisanuki YY, Williams CS, Hammer RE, Richardson JA, Schneider MD, and Yanagisawa M (2003) Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol. Mol Cell Biol 23: 8226-8232.
Miyata S and Haneda T (1994) Hypertrophic growth of cultured neonatal rat heart cells mediated by type 1 angiotensin II receptor. Am J Physiol 266: H2443-H2451.
Molkentin JD and Dorn IG 2nd (2001) Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol 63: 391-426.[CrossRef][Medline]
Mulder P, Richard V, Derumeaux G, Hogie M, Henry JP, Lallemand F, Compagnon P, Mace B, Comoy E, Letac B, et al. (1997) Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics and cardiac remodeling. Circulation 96: 1976-1982.
Ono Y, Ito H, Tamamori M, Nozato T, Adachi S, Abe S, Marumo F, and Hiroe M (2000) Role and relation of p70 S6 and extracellular signal-regulated kinases in the phenotypic changes of hypertrophy of cardiac myocytes. Jpn Circ J 64: 695-700.[CrossRef][Medline]
Oshima Y, Fujio Y, Funamoto M, Negoro S, Izumi M, Nakaoka Y, Hirota H, Yamauchi-Takihara K, and Kawase I (2002) Aldosterone augments endothelin-1-induced cardiac myocyte hypertrophy with the reinforcement of the JNK pathway. FEBS Lett 524: 123-126.[CrossRef][Medline]
Rajapurohitam V, Gan XT, Kirshenbaum LA, and Karmazyn M (2003) The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res 93: 277-279.
Rubanyi GM and Polokoff MA (1994) Endothelins: molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol Rev 46: 325-415.[Medline]
Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, and Sugishita Y (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature (Lond) 384: 353-355.[CrossRef][Medline]
Shubeita HE, McDonough PM, Harris AN, Knowlton KU, Glembotski CC, Brown JH, and Chien KR (1990) Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem 265: 20555-20562.
Simpson P, McGrath A, and Savion S (1982) Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 51: 787-801.
Stewart DJ, Kubac G, Costello KB, and Cernacek P (1991) Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J Am Coll Cardiol 18: 38-43.[Abstract]
Yorikane R, Sakai S, Miyauchi T, Sakurai T, Sugishita Y, and Goto K (1993) Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload. FEBS Lett 332: 31-34.[CrossRef][Medline]
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, P < 0.05 versus PE or AngII (n = 6 group, more than 40 individual cells were counted in each group). A, angiotensin II.
