Cardiovascular Research

Cardiovascular Research 2000 45(3):713-719; doi:10.1016/S0008-6363(99)00370-3
© 2000 by European Society of Cardiology

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Singh, K. Articles by Colucci, W. S. Search for Related Content PubMed PubMed Citation Articles by Singh, K. Articles by Colucci, W. S. Social Bookmarking          What's this?

Copyright © 2000, European Society of Cardiology

Adrenergic regulation of myocardial apoptosis

Krishna Singh, Catherine Communal, Douglas B. Sawyer and Wilson S. Colucci^*

Myocardial Biology Unit and Cardiovascular Division, Boston University Medical Center, Boston Veterans Affairs Medical Center and Boston University School of Medicine, 88 East Newton Street, Boston, MA 02118, USA

^* Corresponding author. Tel.: +1-617-638-8706; fax: +1-617-638-8712 wilson.colucci{at}bmc.org

Received 12 August 1999; accepted 11 October 1999

	Abstract

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
Increased sympathetic nerve activity to the myocardium is a central feature in patients with heart failure. Norepinephrine, the primary transmitter of the sympathetic nervous system, signals via binding to - and β-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac myocytes in vitro demonstrate that β-AR can stimulate apoptosis. Likewise, in transgenic mice overexpression of β₁-AR or Gs is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Whereas β₁-AR stimulate apoptosis in vitro and in vivo, β₂-AR may either stimulate or inhibit apoptosis and myocardial failure depending on the level of expression. Receptors coupling to Gi and Gq may also be able to mediate or modulate apoptosis and the development of myocardial failure, suggesting the potential for interactions between the β-AR system and numerous remodeling stimuli that act through Gi or Gq signaling pathways. It appears likely that the mitogen-activated protein kinase superfamily plays a key role in mediating the actions of adrenergic pathways on myocyte apoptosis. These observations suggest that the adrenergic nervous system plays an important role in the regulation of myocyte apoptosis, and may thus contribute to the development of myocardial failure.

KEYWORDS Adrenergic (ant)agonists; Apoptosis; Autonomic nervous system; G-proteins; Heart failure; Receptors; Signal transduction

	1 Introduction

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
The finding of apoptosis in hearts from patients with end-stage heart failure [1,2] has raised the possibility that apoptosis contributes to the pathophysiology of myocardial failure. Apoptosis of cardiac myocytes during fetal and early postnatal development may play a central role in determining the number of myocytes in the adult heart [3]. However, the apparently limited capacity for regeneration of myocytes in the adult heart suggests that continued myocyte loss due to apoptosis could contribute to progressive myocardial failure.

Increased sympathetic nerve activity in the myocardium is a central feature in patients with heart failure [4,5]. Norepinephrine (NE), the primary transmitter of the sympathetic nervous system, binds to G-protein-coupled adrenergic receptors (AR), of which at least nine subtypes have been identified [6,7]. Here we will focus on the potential role of AR and their associated G-proteins in mediating apoptosis in cardiac myocytes.

	2 NE cardiotoxicity

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
As early as 1959 Rona et al. [8] and others [9–11] observed that chronic exposure of rats to adrenergic agonists caused myocyte necrosis in the absence of obstructive coronary artery narrowing. In 1992, Mann et al. [12] extended these observations to adult feline cardiac myocyte in primary culture. They found that when quiescent rod shaped cardiac myocytes in culture were exposed to NE a large proportion contracted spontaneously, developed hypercontracture and subsequently died over the next 2 to 3 days. This cytotoxic effect of NE, which was associated with the release of creatine kinase, was antagonized by the β-AR antagonist propranolol (Fig. 1), but not the -AR antagonist phentolamine, and was mimicked by the β-AR selective agonist isoproterenol. They further demonstrated that cAMP and calcium influx via verapamil-sensitive channels were necessary for the cytotoxic effect of NE.

View larger version (40K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Norepinephrine (1 µM) decreased the viability of adult cardiac myocytes in culture for 48 (black bars) or 72 h (hatched bars). The toxic effect was fully inhibited by the β-AR antagonist propranolol in a dose-dependent manner. Likewise, propranolol plus the -adrenergic antagonist phentolamine (10 µM) completely blocked the effect of norepinephrine. From Mann et al. [12] with permission. (* P<0.05 vs. control).

 

	3 β-AR stimulation increases myocyte apoptosis

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
3.1 Adult rat cardiac myocytes in vitro
Using adult rat cardiac myocytes in vitro, we found that the cardiotoxic effect of NE was associated with apoptosis [13]. Exposure to NE (10 µM) for 24 h increased genomic DNA fragmentation as analyzed by agarose gel and the percentage of cells that were stained positive by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) staining. These changes were associated with an increase in the percentage of apoptotic cells with hypodiploid DNA content as measured by flow cytometry. The apoptotic effect of NE was abolished by the β-AR antagonist propranolol, but not the -AR antagonist prazosin (Fig. 2). The apoptotic effect of NE was mimicked by the β-AR agonist isoproterenol and by forskolin, a direct activator of adenylyl cyclase. The protein kinase A (PKA) inhibitor H89 likewise blocked the apoptotic effects of NE, as did the L-type calcium channel blocker diltiazem. These studies indicate that NE, acting via the β-AR pathway, stimulates apoptosis in adult cardiac myocytes and that the effect is mediated by the activation of protein kinase A and requires calcium entry via the voltage-dependent calcium channel.

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Stimulation of apoptosis, reflected by the percentage of hypodiploid cells as measured by flow cytometry, in adult rat cardiac myocytes in culture. Norepinephrine (NE; 10 µM) stimulated apoptosis which was inhibited by the β-AR antagonist propranolol but not the 1-AR antagonist prazosin. Isoproterenol and forskolin mimicked the effects of NE to stimulate apoptosis, whereas pretreatment with the protein kinase A (PKA) inhibitor H89 or the L-type calcium channel antagonist diltiazem blocked NE-stimulated apoptosis. From Communal et al. 1998 [13] with permission. (* P<0.05 vs. NE).

 
3.2 Isoproterenol infusion in vivo
In 1998, Shizukuda et al. [14] found a similar effect of β-AR stimulation in vivo. They observed that continuous infusion of isoproterenol for periods of 12 h to 7 days increased the frequency of TUNEL-positive myocytes in the heart at all time points. Most of the TUNEL-positive cardiac myocytes were located in areas of myocardial damage. Pacing to the same heart rate as stimulated by isoproterenol did not increase the number of apoptotic myocytes, suggesting that apoptosis was not due to tachycardia.

	4 Differential effects of β-AR subtypes

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
4.1 β₁- vs. β₂-AR
Recently, using adult rat cardiac myocytes in vitro we found that the β₁-AR selective antagonist CGP 20712A completely prevented NE-stimulated apoptosis, whereas the β₂-AR selective antagonist ICI 118,551 potentiated the amount of NE-stimulated apoptosis [15]. Interestingly, in this system pretreatment with pertussis toxin (PTX) to inactivate Gi increased the magnitude of β-AR stimulated apoptosis, and thus mimicked the effect of a β₂-AR selective antagonist. Conversely, we found that pretreatment with carbachol, which stimulates Gi via activation of M₂ muscarinic receptors, inhibited β-AR-mediated apoptosis [15]. Thus, at least in this experimental model, NE stimulates apoptosis via β₁-AR and inhibits apoptosis via β₂-AR. The later action appears to involve a PTX-sensitive G-protein, most likely Gi.

The opposing effects of β₁- vs. β₂-AR on myocyte apoptosis may be due to the differential signaling of these receptors subtypes. Although both β₁- and β₂-AR couple to Gs and exert effects via adenylyl cyclase and cAMP, a component of the effects of β₂-AR-stimulation may oppose the actions of Gs and appears to be independent of Gs and cAMP [16–18]. These observations may relate to the recent demonstration that β₂-AR, but not β₁-AR, also couple to a PTX-sensitive G-protein, presumably Gi [19]. For example, in cardiac myocytes pretreatment with PTX potentiates the response to β₂-AR, not β₁-AR, stimulation [19,20]. It is possible that coupling of β₂-AR to Gi could oppose actions mediated by the coupling of β₁- and β₂-AR to Gs. Interestingly, the coupling of β₂-AR to Gi may be regulated by a Gs-mediated, protein kinase A-dependent phosphorylation of the β₂-AR which favors coupling to Gi [21]. In the adult rat cardiac myocyte system that we studied, the net effect of NE is to increase the frequency of apoptosis, presumably reflecting the predominance of β₁-AR in these cells [13,15].

4.2 β₃-AR
Relatively little is known about the functional role of β₃-AR in the myocardium. Since they appear to act in part by stimulation of nitric oxide [22], β₃-AR have the potential to modify calcium influx, reactive oxygen species and a variety of biochemical pathways that might influence the rate of apoptosis.

	5 Neonatal rat cardiac myocytes

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
It is not clear whether β-AR stimulation affects the frequency of apoptosis in neonatal rat ventricular myocytes. In one report, NE alone had no effect on the frequency of apoptosis, but inhibited apoptosis stimulated by atrial natriuretic peptide (ANP) [23]. The antiapoptotic effects of NE on ANP-stimulated apoptosis were blocked by propranolol but not by the ₁-selective antagonist terazosin. These antiapoptotic effects of NE were mimicked by isoproterenol and dibutryl-cAMP.

However, Iwai-kanai et al. have recently reported that in neonatal rat cardiac myocytes β-adrenergic stimulation increases apoptosis [24]. The apoptotic action of β-adrenergic stimulation was opposed by concurrent treatment with an -adrenergic agonist. The reason for the discrepant findings in neonatal cardiac myocytes remains to be determined, but may relate to differences in the cell culture conditions.

	6 Adrenergic receptor overexpression in mouse myocardium

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
Work with transgenic mice that overexpress AR receptors and G-proteins in the myocardium has provided insights into the mechanism by which adrenergic activation can affect myocyte phenotype.

6.1 β₁-AR overexpressing mice
At least two groups have made mice that overexpress the β₁-AR in the myocardium under the control of the -myosin heavy chain (MHC) promoter [25,26]. In both cases the transgenic mice are born and develop normally. They exhibit increased cardiac contractility at a young age associated with myocyte hypertrophy [26]. However, by about 9 months of age they develop left ventricular dilation with decreased contractile function [25]. Recently, Port et al. (unpublished data) observed that mice overexpressing β₁-AR in the myocardium have an increased frequency of apoptotic myocytes as measured by in situ TUNEL-staining.

6.2 β₂-AR overexpressing mice
Mice overexpressing β₂-AR in the heart also exhibit increased contractile function when young [19]. In contrast to β₁-AR overexpressing mice they do not appear to develop myocardial dysfunction with age, although the duration of these observations (approximately 4 months) is not sufficient to conclude that an adverse effect will not occur with time.

However, in mice that overexpress Gq in the myocardium, the concurrent overexpression of β₂-AR exerts biphasic, level-dependent effects on phenotype. As discussed below, myocardial overexpression of wild-type Gq (Gq-25) results in cardiac hypertrophy, fetal gene expression and progressive ventricular failure [27–30]. With the concurrent overexpression of a low level of β₂-AR there is rescue of the phenotype with improved ventricular function and reduced fetal gene expression [31]. In contrast, with the concurrent overexpression of a high level of β₂-AR there is marked acceleration of the phenotype with rapid progression to heart failure and death at 5 weeks of age. Mice expressing an intermediate level of β₂-AR had increased adenylyl cyclase activity but no change in hypertrophy, fetal gene expression or ventricular function. These data are consistent with the thesis that β₂-AR exert counterbalancing effects on phenotype. At low levels of receptor expression, there is improved ventricular function and possibly coupling to a protective signaling mechanism, whereas at high levels of receptor expression excessive activation of adenylyl cyclase tips the balance in favor of the failure phenotype.

6.3 ₁-AR overexpressing mice
Mice that overexpress a constitutively-active _1B-AR in the myocardium develop myocardial hypertrophy with myocyte widening and increased expression of ANP at 10 weeks of age [32]. In contrast, expression of a wild-type _1B-AR does not cause myocardial hypertrophy despite increased expression of ANP [33,34]. In these mice the contractile response to β-AR stimulation was blunted, as was basal and stimulated adenylyl cyclase activity in isolated membranes. Of note, the attenuated β-AR signaling was reversed by treatment of mice with PTX, suggesting that _1B-AR overexpression had led to increased activity of Gi.

	7 G-protein overexpression in mouse myocardium

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
The intracellular signaling by which sympathetic nerve activity regulates myocardial function involves coupling of receptors to GTP-binding proteins (G-proteins) [6]. Both β₁- and β₂-AR signal through coupling of the stimulatory G-protein (Gs) to adenylyl cyclase, leading to production of cAMP. It has recently been shown that β₂-AR can also couple to other signaling pathways independent of cAMP or Gs, and in particular, to a PTX-sensitive pathway thought to be mediated by Gi [20,21,35,36]. The ₁-AR couples primarily through Gq and Gi [6].

7.1 Gs overexpressing mice
Vatner and colleagues developed transgenic mice with an approximately threefold overexpression of Gs in the myocardium associated with a modest (88%) increase in Gs activity [37]. Although there was no increase in basal or stimulated adenylyl cyclase activity, there was a decrease in the lag time to activation by GppNHp. Furthermore, the ionotropic and chronotropic responses to exogenous sympathetic stimulation were increased in the transgenic animals [37]. By 16 months of age there was myocardial degeneration and atrophy, replacement fibrosis and hypertrophy of myocytes with increased cross-sectional area [37]. These histological changes were associated with chamber dilation, reduced ejection fraction and increased mortality [38].

Histochemistry and electron microscopy revealed the presence of myocytes with abnormal nuclei characterized by chromatin condensation, vacuole formation and irregularity of the nuclear membrane [39]. TUNEL-staining revealed an increase in the number of TUNEL-positive myocyte nuclei in the 15–18 month old transgenic mice (Fig. 3) whereas mice 4–7 months of age exhibited only rare TUNEL-positive cells in a frequency not different from wild-type animals. Similarly, cardiac myocytes isolated from newborn Gs transgenic mice showed an increased number of TUNEL-positive nuclei and internucleosomal DNA when treated with the β-agonist isoproterenol [39]. These studies led to the suggestion that excessive activation of Gs could contribute to the development of cardiomyopathy due to apoptosis.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Increased apoptosis, as measured by TUNEL-staining, in myocardium from Gs overexpressing mice. The number of TUNEL-positive myocyte nuclei was increased in the older (15–18 months old) transgenic hearts, but not in the younger (4–7 months old) Gs transgenic hearts, as compared to age-matched wild-type (WT) hearts. Older transgenic mice developed left ventricular dilation, reduced systolic function and died of heart failure. From Geng et al. 1999 [39] with permission. (* P<0.05).

 
7.2 Gq overexpressing mice
NE induces hypertrophy in cardiac myocytes in vitro via ₁-AR which couple to Gq, thereby activating phospholipase C, inositol 1,4,5-triphosphate and protein kinase C [6]. Transfection of neonatal cardiac myocytes with constitutively-active Gq increased ANP expression, whereas injection of an neutralizing Gq antibody blocked ₁-AR-stimulated hypertrophy and ANP expression [40]. Gq couples to several other agonists including angiotensin II and endothelin [41].

Dorn and colleagues developed mice that overexpress wild-type Gq in the myocardium under the control of the -myosin heavy chain promoter [27,29,30]. In heterozygous animals with a four- to fivefold increased level of Gq there was myocardial hypertrophy [30] associated with a normal life span [29], although ventricular myocytes isolated from these mice exhibited depressed contractility [29]. Interestingly female mice overexpressing Gq developed a fulminant form of peripartal heart failure associated with myocyte apoptosis and fibrosis [27]. However, when heterozygotes were crossed, yielding mice with an eightfold increase in myocardial Gq levels, the animals died from heart failure at an average age of 11 weeks [27]. Of note, these animals had a marked increase in the frequency of apoptotic myocytes, leading to the suggestion that apoptosis had contributed to myocardial failure.

It was further found that if mice overexpressing Gq were exposed to pressure overload (aortic constriction) they developed a different phenotype than wild-type animals. In nontransgenic mice aortic constriction resulted in concentric hypertrophy with maintained cardiac performance. In marked contrast, in Gq overexpressing mice pressure overload resulted in eccentric hypertrophy associated with depressed contractile function and hemodynamic decompensation leading to heart failure [29].

Mende et al. [28] developed transgenic mice expressing an epitope-tagged, constitutively-active mutant of Gq under the control of the -myosin heavy chain promoter. They found that the expression of the epitope-tagged transgene decreased over time and was not detectable by 10 weeks. Nevertheless, the animals developed cardiac hypertrophy, progressive ventricular dilation and died from heart failure at 8–30 weeks of age, leading to the suggestion that even transient overexpression of Gq could initiate a pathological sequence leading to cardiac decompensation.

7.3 Mice overexpressing Gq inhibitor
Transgenic mice with cardiac specific expression of a Gq inhibitor transgene (carboxy-terminus of Gq, residues 305–359) exhibited less hypertrophy in response to pressure overload (transverse aortic constriction) than did wild-type mice, further supporting a role for Gq in the regulation of myocardial hypertrophy [42].

	8 Role of mitogen-activated protein kinases (MAPKs)

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
The MAPK superfamily has been shown to play an important role in the regulation of cardiac myocyte hypertrophy and apoptosis [43]. The MAPK superfamily includes extracellularly responsive kinases (ERKs) and the two stress-responsive MAPK (SR-MAPKs) subfamilies, the c-Jun N-terminal kinases (JNKs) and p38-kinases [43]. JNKs are 46 or 54 kDa proteins. Six isoforms (1, 2, β1, β2, and ) of p38-kinases have been cloned. Human heart expresses primarily the and β isoforms of p38-kinase [44].

G-protein coupled receptors have been shown to activate ERKs and the SR-MAPKs [21,41,43]. Of particular interest is the demonstration by Daaka et al. [21] that PKA-mediated phosphorylation of β₂-AR induces coupling to Gi, which initiates signaling events through β-subunits to activate ERK pathways. β-Subunits are also known to activate JNKs via Ras in a Rac1-dependent manner [45]. Likewise, expression of a constitutively-active Gi-2 subunit activates SR-MAPKs including p38 kinases and JNKs [46]. These observations suggest that β₂-AR are capable of activating the MAPKs module via coupling with Gi.

The SR-MAPKs appear to play a key role in regulation of hypertrophy and apoptosis in cardiac myocytes. In neonatal rat ventricular myocytes the expression of constitutively-active MAPK kinase (MKK7), an upstream activator of JNKs, caused sarcomeric organization, increased cell size and enhanced the expression of ANP [47]. The expression of a constitutively-active p38β isoform caused a hypertrophic response, whereas expression of a constitutively-active p38 isoform caused apoptosis [48]. It appears that activation of the ERKs cascade is not sufficient for triggering a hypertrophic response for G-protein coupled receptors [49]. The relative roles of ERKs and SR-MAPKs in stimulating or opposing apoptosis remains to be determined.

	9 Clinical implications

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
β-AR antagonists have been shown to improve left ventricular remodeling, ameliorate symptoms and improve survival in patients with systolic myocardial failure. Basic research in cardiac myocytes in vitro and transgenic mice demonstrates that β-AR and Gs can stimulate myocyte apoptosis associated with development of the failure phenotype. Thus, the data so far support the thesis that increased sympathetic tone contributes to progressive myocardial failure in patients via stimulation of the β-AR/Gs pathway.

Certain caveats should be kept in mind. First, these studies do not prove that the deleterious effect of β-AR stimulation is due to apoptosis, or conversely, that the beneficial effect of β-AR blockade is due to reduced apoptosis. Second, the specificity of the indices of apoptosis commonly used in most studies is not certain. For example, it has been pointed out that a positive TUNEL reaction can reflect DNA repair [50] or oncocytic necrosis [51].

Likewise, many issues remain to be clarified. While β₁-AR seem only to stimulate apoptosis, β₂-AR appear capable of either stimulating or inhibiting apoptosis, and may accelerate or retard the development of myocardial failure. It further appears that receptors coupling to Gi and Gq have the potential to mediate or modulate apoptosis and the development of myocardial failure, suggesting the potential for interactions between the β-AR system and numerous remodeling stimuli that act through Gi or Gq signaling. Finally, it appears likely that the MAPK superfamily plays a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and phenotype.

Taken together, these exciting new insights suggest that greater understanding of the mechanism by which the adrenergic nervous system regulates myocyte apoptosis will lead to even further improvement in the treatment of heart failure.

Time for primary review 40 days.

	Acknowledgments

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 
This work is supported by NIH grants HL57947 (KS); HL42539, HL52320 and HL61639 (WSC); HL03878 (DBS); and by a Fellowship (CC) and Grant-in-Aid (KS, DBS) from the American Heart Association, New England Affiliate, and a Merit Review Grant from the Department of Veterans Affairs (KS).

	References

Top Abstract 1 Introduction 2 NE cardiotoxicity 3 β-AR stimulation... 4 Differential effects of... 5 Neonatal rat cardiac... 6 Adrenergic receptor... 7 G-protein overexpression in... 8 Role of mitogen-activated... 9 Clinical implications Acknowledgments References

 

1. Narula J., Haider N., Virmani R., et al. Apoptosis in myocytes in end-stage heart failure. New Engl J Med (1996) 335:1182–1189.[Abstract/Free Full Text]
2. Olivetti G., Abbi R., Quaini F., et al. Apoptosis in the failing human heart. New Engl J Med (1997) 336:1131–1141.[Abstract/Free Full Text]
3. Haunstetter A., Izumo S. Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res (1998) 82:1111–1129.[Free Full Text]
4. Hasking G.J., Esler M.D., Jennings G.L., Dewar E., Lambert G. Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects. Circulation (1988) 78:516–521.[Abstract/Free Full Text]
5. Swedberg K., Viquerat C., Rouleau J.L., et al. Comparison of myocardial catecholamine balance in chronic congestive heart failure and in angina pectoris without failure. Am J Cardiol (1984) 54:783–786.[CrossRef][Web of Science][Medline]
6. Hadcock J.R., Malbon C.C. Agonist regulation of gene expression of adrenergic receptors and G-proteins. J Neurochem (1993) 60:1–9.[CrossRef][Web of Science][Medline]
7. Rockman H.A., Koch W.J., Lefkowitz R.J. Cardiac function in genetically engineered mice with altered adrenergic receptor signaling. Am J Physiol (1997) 272:H1553–H1559.[Web of Science][Medline]
8. Rona G., Chappel C.I., Balazs T., Gaudry R. An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Am Med Assoc Arch Pathol (1959) 67:443–455.
9. Reichenbach D.D., Benditt E.P. Catecholamine and cardiomyopathy: the pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol (1970) 1:125–150.[CrossRef]
10. Ferrans V.J., Hibbs R.G., Black W.C., Weilbaecher D.G. Isoproterenol-induced myocardial necrosis: a histochemical and electron microscopic study. Am Heart J (1999) 68:71–90.
11. Teerlink J.R., Pfeffer J.M., Pfeffer M.A. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res (1994) 75:105–113.[Abstract/Free Full Text]
12. Mann D.L., Kent R.L., Parsons B., Cooper G. IV. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation (1992) 85:790–804.[Abstract/Free Full Text]
13. Communal C., Singh K., Pimentel D.R., Colucci W.S. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation (1998) 98:1329–1334.[Abstract/Free Full Text]
14. Shizukuda Y., Buttrick P.M., Geenen D.L., et al. Beta-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol (1998) 275:H961–968.[Web of Science][Medline]
15. Communal C., Singh K., Colucci W.S. Gi protein protects adult rat ventricular myocytes from beta-adrenergic receptor-stimulated apoptosis in vitro. Circulation (1998) 98:I742.
16. Xiao R.P., Hohl C., Altschuld R., et al. Beta 2-adrenergic receptor-stimulated increase in cAMP in rat heart cells is not coupled to changes in Ca²⁺ dynamics, contractility, or phospholamban phosphorylation. J Biol Chem (1994) 269:19151–19156.[Abstract/Free Full Text]
17. Xiao R.P., Lakatta E.G. Beta 1-adrenoceptor stimulation and beta 2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca²⁺, and Ca²⁺ current in single rat ventricular cells. Circ Res (1993) 73:286–300.[Abstract/Free Full Text]
18. Altschuld R.A., Starling R.C., Hamlin R.L., et al. Response of failing canine and human heart cells to beta 2-adrenergic stimulation. Circulation (1995) 92:1612–1618.[Abstract/Free Full Text]
19. Xiao R.P., Avdonin P., Zhou Y.Y., et al. Coupling of beta₂-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res (1999) 84:43–52.[Abstract/Free Full Text]
20. Xiao R.P., Ji X., Lakatta E.G. Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G-protein in cardiac myocytes. Mol Pharmacol (1995) 47:322–329.[Abstract]
21. Daaka Y., Luttrell L.M., Lefkowitz R.J. Switching of the coupling of the beta₂-adrenergic receptor to different G-proteins by protein kinase A. Nature (1997) 390:88–91.[CrossRef][Medline]
22. Gauthier C., Leblais V., Kobzik L., et al. The negative ionotropic effect of beta₃-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest (1998) 102:1377–1384.[Web of Science][Medline]
23. Wu C.F., Bishopric N.H., Pratt R.E. Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem (1997) 272:14860–14866.[Abstract/Free Full Text]
24. Iwai-kanai E., Hasegawa K., Araki M., et al. - And β-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation (1999) 100:305–311.[Abstract/Free Full Text]
25. Port J.D., Weinberger H.D., Bisognano J.D., et al. Echocardiographic and histopathological characterization of young and old transgenic mice over-expressing the human beta₁-adrenergic receptor. J Am Coll Cardiol (1998) 31:177A.
26. Engelhardt S., Hein L., Wiesmann F., Lohse M.J. Progressive hypertrophy and heart failure in beta₁-adrenergic receptor transgenic mice [In Process Citation]. Proc Natl Acad Sci USA (1999) 96:7059–7064.[Abstract/Free Full Text]
27. Adams J.W., Sakata Y., Davis M.G., et al. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci USA (1998) 95:10140–10145.[Abstract/Free Full Text]
28. Mende U., Kagen A., Cohen A., et al. Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc Natl Acad Sci USA (1998) 95:13893–13898.[Abstract/Free Full Text]
29. Sakata Y., Hoit B.D., Liggett S.B., Walsh R.A., Dorn G.W. II. Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation (1998) 97:1488–1495.[Abstract/Free Full Text]
30. D’Angelo D.D., Sakata Y., Lorenz J.N., et al. Transgenic Gq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA (1997) 94:8121–8126.[Abstract/Free Full Text]
31. Dorn G.W.I., Tepe N.M., Lorenz J.N., Koch W.J., Liggett S.B. Low- and high-level transgenic expression of β₂-adrenergic receptors differentially affect cardiac hypertrophy and function in Gq-overexpressing mice. Proc Natl Acad Sci USA (1999) 96:6400–6405.[Abstract/Free Full Text]
32. Milano C.A., Dolber P.C., Rockman H.A., et al. Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci USA (1994) 91:10109–10113.[Abstract/Free Full Text]
33. Akhter S.A., Milano C.A., Shotwell K.F., et al. Transgenic mice with cardiac overexpression of alpha_1B-adrenergic receptors. In vivo alpha₁-adrenergic-mediated regulation of beta-adrenergic signaling. J Biol Chem (1997) 272:21253–21259.[Abstract/Free Full Text]
34. Grupp I.L., Lorenz J.N., Walsh R.A., Boivin G.P., Rindt H. Overexpression of _1B-adrenergic receptor induces left ventricular dysfunction in the absence of hypertrophy. Am J Physiol (1998) 275:H1338–H1350.[Web of Science][Medline]
35. Pavoine C., Magne S., Sauvadet A., Pecker F. Evidence for a beta₂-adrenergic/arachidonic acid pathway in ventricular cardiomyocytes. Regulation by the beta₁-adrenergic/cAMP pathway. J Biol Chem (1999) 274:628–637.[Abstract/Free Full Text]
36. Xiao R.P., Tomhave E.D., Wang D.J., et al. Age-associated reductions in cardiac beta₁- and beta₂-adrenergic responses without changes in inhibitory G-proteins or receptor kinases. J Clin Invest (1998) 101:1273–1282.[Web of Science][Medline]
37. Iwase M., Bishop S.P., Uechi M., et al. Adverse effects of chronic endogenous sympathetic drive induced by cardiac Gs alpha overexpression. Circ Res (1996) 78:517–524.[Abstract/Free Full Text]
38. Iwase M., Uechi M., Vatner D.E., et al. Cardiomyopathy induced by cardiac Gs alpha overexpression. Am J Physiol (1997) 272:H585–H589.[Web of Science][Medline]
39. Geng Y.J., Ishikawa Y., Vatner D.E., et al. Apoptosis of cardiac myocytes in Gsalpha transgenic mice. Circ Res (1999) 84:34–42.[Abstract/Free Full Text]
40. LaMorte V.J., Thorburn J., Absher D., et al. Gq- and Ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following alpha 1-adrenergic stimulation. J Biol Chem (1994) 269:13490–13496.[Abstract/Free Full Text]
41. Force T., Bonventre J.V. Growth factors and mitogen-activated protein kinases. Hypertension (1998) 31:152–161.[Abstract/Free Full Text]
42. Akhter S.A., Luttrell L.M., Rockman H.A., et al. Targeting the receptor–Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science (1998) 280:574–577.[Abstract/Free Full Text]
43. Sugden P.H., Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res (1998) 83:345–352.[Free Full Text]
44. Jiang Y., Gram H., Zhao M., et al. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinase, p38. J Biol Chem (1997) 272:30122–30128.[Abstract/Free Full Text]
45. Coso O.A., Montaner S., Fromm C., et al. Signaling from G-protein-coupled receptors to the c-Jun promoter involves the MEF₂ transcription factor. Evidence for a novel c-Jun amino-terminal kinase-independent pathway. J Biol Chem (1997) 272:20691–20697.[Abstract/Free Full Text]
46. Guo J.H., Wang H.Y., Malbon C.C. Conditional, tissue-specific expression of Q205L Galphai2 in vivo mimics insulin activation of c-Jun N-terminal kinase and p38 kinase. J Biol Chem (1998) 273:16487–16493.[Abstract/Free Full Text]
47. Wang Y., Su B., Sah V.P., et al. Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol Chem (1998) 273:5423–5426.[Abstract/Free Full Text]
48. Wang Y., Huang S., Sah V.P., et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem (1998) 273:2161–2168.[Abstract/Free Full Text]
49. Post G.R., Goldstein D., Thuerauf D.J., Glembotski C.C., Brown J.H. Dissociation of p44 and p42 mitogen-activated protein kinase activation from receptor-induced hypertrophy in neonatal rat ventricular myocytes. J Biol Chem (1996) 271:8452–8457.[Abstract/Free Full Text]
50. Kanoh M., Takemura G., Misao J., et al. Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in hearts with dilated cardiomyopathy. Circulation (1999) 99:2757–2764.[Abstract/Free Full Text]
51. Buja L.M., Entman M.L. Modes of myocardial cell injury and cell death in ischemic heart disease. Circulation (1998) 98:1355–1357.[Free Full Text]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				H. Zheng, Y.-F. Li, W. Wang, and K. P. Patel Enhanced angiotensin-mediated excitation of renal sympathetic nerve activity within the paraventricular nucleus of anesthetized rats with heart failure Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2009; 297(5): R1364 - R1374. [Abstract] [Full Text] [PDF]

				J. H. Rennison and D. R. Van Wagoner Impact of Dietary Fatty Acids on Cardiac Arrhythmogenesis Circ Arrhythm Electrophysiol, August 1, 2009; 2(4): 460 - 469. [Full Text] [PDF]

				K. S. Moshal, S. M. Tipparaju, T. P. Vacek, M. Kumar, M. Singh, I. E. Frank, P. K. Patibandla, N. Tyagi, J. Rai, N. Metreveli, et al. Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemia Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H890 - H897. [Abstract] [Full Text] [PDF]

				I. Mikaelian, D. Coluccio, K. T. Morgan, T. Johnson, A. L. Ryan, E. Rasmussen, R. Nicklaus, C. Kanwal, H. Hilton, K. Frank, et al. Temporal Gene Expression Profiling Indicates Early Up-regulation of Interleukin-6 in Isoproterenol-induced Myocardial Necrosis in Rat Toxicol Pathol, February 1, 2008; 36(2): 256 - 264. [Abstract] [Full Text] [PDF]

				P. Krishnamurthy, V. Subramanian, M. Singh, and K. Singh {beta}1 Integrins Modulate {beta}-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling Hypertension, April 1, 2007; 49(4): 865 - 872. [Abstract] [Full Text] [PDF]

				S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT J. Biol. Chem., November 18, 2005; 280(46): 38505 - 38512. [Abstract] [Full Text] [PDF]

				J. G. Burniston, L.-B. Tan, and D. F. Goldspink {beta}2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle J Appl Physiol, April 1, 2005; 98(4): 1379 - 1386. [Abstract] [Full Text] [PDF]

				P. Camelliti, T. K. Borg, and P. Kohl Structural and functional characterisation of cardiac fibroblasts Cardiovasc Res, January 1, 2005; 65(1): 40 - 51. [Abstract] [Full Text] [PDF]

				B. N. Eigel, H. Gursahani, and R. W. Hadley Na+/Ca2+ exchanger plays a key role in inducing apoptosis after hypoxia in cultured guinea pig ventricular myocytes Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1466 - H1475. [Abstract] [Full Text] [PDF]

				G.-C. Fan, G. Chu, B. Mitton, Q. Song, Q. Yuan, and E. G. Kranias Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits {beta}-Agonist-Induced Cardiac Apoptosis Circ. Res., June 11, 2004; 94(11): 1474 - 1482. [Abstract] [Full Text] [PDF]

				E. S. Bachman, T. G. Hampton, H. Dhillon, I. Amende, J. Wang, J. P. Morgan, and A. N. Hollenberg The Metabolic and Cardiovascular Effects of Hyperthyroidism Are Largely Independent of {beta}-Adrenergic Stimulation Endocrinology, June 1, 2004; 145(6): 2767 - 2774. [Abstract] [Full Text] [PDF]

				Y.-C. Fu, C.-S. Chi, S.-C. Yin, B. Hwang, Y.-T. Chiu, and S.-L. Hsu Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF{alpha}-caspase signaling pathway Cardiovasc Res, June 1, 2004; 62(3): 558 - 567. [Abstract] [Full Text] [PDF]

				Y.-F. Li, K. G. Cornish, and K. P. Patel Alteration of NMDA NR1 Receptors Within the Paraventricular Nucleus of Hypothalamus in Rats With Heart Failure Circ. Res., November 14, 2003; 93(10): 990 - 997. [Abstract] [Full Text] [PDF]

				Y. Ogata, M. Takahashi, S. Ueno, K. Takeuchi, T. Okada, H. Mano, S. Ookawara, K. Ozawa, B. C. Berk, U. Ikeda, et al. Antiapoptotic Effect of Endothelin-1 in Rat Cardiomyocytes In Vitro Hypertension, May 1, 2003; 41(5): 1156 - 1163. [Abstract] [Full Text] [PDF]

				G. M. Felker, R. L. Benza, A. B. Chandler, J. D. Leimberger, M. S. Cuffe, R. M. Califf, M. Gheorghiade, C. M. O'Connor, and OPTIME-CHF Investigators Heart failure etiology and response tomilrinone in decompensated heart failure: Results from the OPTIME-CHF study J. Am. Coll. Cardiol., March 19, 2003; 41(6): 997 - 1003. [Abstract] [Full Text] [PDF]

				R H Arnold, E Kotlyar, C Hayward, A M Keogh, and P S Macdonald Relation between heart rate, heart rhythm, and reverse left ventricular remodelling in response to carvedilol in patients with chronic heart failure: a single centre, observational study Heart, March 1, 2003; 89(3): 293 - 298. [Abstract] [Full Text] [PDF]

				N. A Turner, K. E Porter, W. H.T Smith, H. L White, S. G Ball, and A. J Balmforth Chronic {beta}2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism Cardiovasc Res, March 1, 2003; 57(3): 784 - 792. [Abstract] [Full Text] [PDF]

				D. J. Drucker Glucagon-Like Peptides: Regulators of Cell Proliferation, Differentiation, and Apoptosis Mol. Endocrinol., February 1, 2003; 17(2): 161 - 171. [Abstract] [Full Text] [PDF]

				B. Yusta, J. Estall, and D. J. Drucker Glucagon-like Peptide-2 Receptor Activation Engages Bad and Glycogen Synthase Kinase-3 in a Protein Kinase A-dependent Manner and Prevents Apoptosis following Inhibition of Phosphatidylinositol 3-Kinase J. Biol. Chem., July 5, 2002; 277(28): 24896 - 24906. [Abstract] [Full Text] [PDF]

				S. Goldstein Benefits of {beta}-Blocker Therapy for Heart Failure: Weighing the Evidence Arch Intern Med, March 25, 2002; 162(6): 641 - 648. [Abstract] [Full Text] [PDF]

				A. Gonzalez, B. Lopez, S. Ravassa, R. Querejeta, M. Larman, J. Diez, and M. A. Fortuno Stimulation of Cardiac Apoptosis in Essential Hypertension: Potential Role of Angiotensin II Hypertension, January 1, 2002; 39(1): 75 - 80. [Abstract] [Full Text] [PDF]

				E. Devic, Y. Xiang, D. Gould, and B. Kobilka beta -Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from beta 1 and beta 2 Adrenoceptor Knockout Mice Mol. Pharmacol., September 1, 2001; 60(3): 577 - 583. [Abstract] [Full Text] [PDF]

				M. Flesch, S. Ettelbruck, S. Rosenkranz, C. Maack, B. Cremers, K.-D. Schluter, O. Zolk, and M. Bohm Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in {beta}-adrenoceptor density and systolic function in rat cardiac myocytes Cardiovasc Res, February 1, 2001; 49(2): 371 - 380. [Abstract] [Full Text] [PDF]

				M. Borgers, L.-M. Voipio-Pulkki, and S. Izumo Apoptosis Cardiovasc Res, February 1, 2000; 45(3): 525 - 527. [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Singh, K. Articles by Colucci, W. S. Search for Related Content PubMed PubMed Citation Articles by Singh, K. Articles by Colucci, W. S. Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics