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Cardiovascular Research Advance Access originally published online on November 21, 2007
Cardiovascular Research 2008 77(3):452-462; doi:10.1093/cvr/cvm078
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Cardiac {alpha}1-adrenergic drive in pathological remodelling

Elizabeth A. Woodcock1, Xiao-Jun Du2, Melissa E. Reichelt3 and Robert M. Graham3,4,*

1 Cellular Biochemistry, Baker Heart Research Institute, Melbourne, Victoria 3004, Australia
2 Experimental Cardiology Laboratories, Baker Heart Research Institute, Melbourne, Victoria 3004, Australia
3 Molecular Cardiology and Biophysics Program, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia
4 University of New South Wales, Kensington, New South Wales 2033, Australia

* Corresponding author. Tel: +61 2 9295 8502; fax: +61 2 9295 8501. E-mail address: b.graham{at}victorchang.edu.au

Received 21 June 2007; revised 16 November 2007; accepted 19 November 2007

Time for primary review: 29 days


   Abstract
Top
 Abstract
1. Introduction
 2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
 5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
 References
 
The heart is richly innervated by sympathetic nerves, and both acute and chronic regulation of cardiac function via sympathetically released catecholamines acting on cardiomyocyte adrenergic receptors (ARs), is critical for circulatory homeostasis. Cardiomyocytes express {alpha}1A- and {alpha}1B-, and β1- and β2-AR subtypes, which are all members of the G-protein-coupled receptor superfamily that signal via interaction with heterotrimeric G-proteins. Cardiac function – both inotropy and chronotropy – is regulated predominantly by β1-AR. Activation of {alpha}1-ARs also results in increased contractility, as well as changes in the electrophysiological properties and metabolic responses of the heart. Nonetheless, there is little evidence that cardiac {alpha}1-ARs play a major functional role under normal physiological conditions. In pathological settings, {alpha}1-ARs may function in a compensatory fashion to maintain cardiac inotropy when the β-AR system is downregulated and uncoupled from G-proteins and effectors. In addition, as we consider here, recent evidence from clinical studies and from genetically engineered animal models indicates that {alpha}1-ARs are importantly involved in both developmental cardiomyocyte growth, as well as pathological hypertrophy. In the presence of pressure overload or with myocardial infarction, activation of {alpha}1-ARs, particularly the {alpha}1A-subtype, also appears to produce important pro-survival effects at the level of the cardiomyocyte, and to protect against maladaptive cardiac remodelling and decompensation to heart failure.

KEYWORDS Adrenergic; Remodelling; Transgenic; Knockout; Cardiac; Hypertrophy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
 5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
 References
 
Formation and remodelling of the mammalian heart involves complex developmentally regulated programs of growth in which functional demand is matched by hyperplastic increases in cardiac size. Whilst cardiomyocyte proliferation augments ventricular mass in utero,1 proliferative capabilities cease soon after birth.2 In the immediate post-natal period, ventricular cardiomyocytes exit the cell cycle and become binucleated as a result of dissociation of the previously tightly coupled processes of karyokinesis (nuclear division) and cytokinesis (cell division). Thereafter, in response to the increased haemodynamic burden of the growing organism or in response to increased physiological demand (e.g. exercise or pregnancy), cardiac mass increases by an adaptive enlargement in cardiomyocyte size. This results in a change in left ventricular (LV) geometry (that is, an increase in LV mass index with normal relative wall thickness) [Note: these changes in LV geometry are also referred to as ‘eccentric’ and ‘concentric’, respectively. However, these morphological descriptors are inexact as they do not always correlate with the aetiology of the hypertrophy. For a detailed consideration of physiological vs. pathological hypertrophy (see Dorn, 2007).], resulting from volume overload-induced cardiomyocyte lengthening, without activation of ‘foetal’ genes3 (discussed later), and with preservation of contractile function, known as physiological hypertrophy.4–6 In contrast, non-mitotic growth of ventricular cardiomyocytes is observed in the adult heart in response to an increase in workload, as occurs, for example, with hypertension, certain types of valvular heart disease, and in the spared myocardium following myocardial infarction. In this pathological form of hypertrophy, however, cardiomyocyte growth is associated with fibrosis, activation of a specific subset of ‘foetal’ genes normally expressed only during embryonic life and, in some instances, disorganization of the contractile apparatus or myofibrils.7–9 Although initially adaptive, the remodelling of LV geometry observed with pathological hypertrophy (refer the above-given ‘Note'), together with the metabolic penalty imposed by the diffusion barrier associated with increased cardiomyocyte width (cross-sectional area) and interstitial fibrosis that is not matched by appropriate angiogenesis, leads to impaired cardiac function that can progress to overt heart failure and even death.10

Factors regulating contractility, including neurohumoural activation acting via catecholamines and cardiomyocyte {alpha}- and β-adrenergic receptors (ARs), can initiate pathological hypertrophy and influence cardiac remodelling.11 Although β-ARs, particularly the β1-subtype, have been widely studied in terms of their regulation of both inotropic and chronotropic contractile function and their role in cardiac hypertrophy, regulation of cardiac function by {alpha}1-ARs and their involvement in hypertrophic cardiomyocyte growth have received less attention, and until recently have been poorly understood. Recent clinical studies as well as studies in genetically engineered animal models now provide support for an important role of {alpha}1-ARs in maintaining cardiac contractility under pathological conditions, such as ischaemia or pathological hypertrophy, that are associated with decreased β1-AR function.12 Nevertheless, apparently conflicting data have come from clinical trials showing a distinct advantage for an adrenergic inhibitor that blocks both {alpha}1- and β-ARs compared with a selective β1-blocker, whereas cardiovascular events are increased in hypertensive and heart failure patients treated with a selective {alpha}1-AR antagonist. Here these issues are considered in light of the pharmacology and haemodynamic effects of the various AR blockers used. In addition, we consider data from genetically engineered animal models in which {alpha}1-ARs have been deleted or overexpressed (Table 1). Although, data from studies of these models must be considered with caution (In addition to the specific caveats regarding genetically engineered models considered in the review, some other considerations with transgenic models include the possibility that the phenotypes observed are not due to expression of the transgene per se, but to insertion into another gene or its regulatory sequence, which may result in its inactivation or altered expression. To obviate this issue, several different transgenic lines are generally developed to confirm that the phenotype is qualitatively similar in all of them. Overexpression of a transgene may also lead to spurious protein-protein interactions, although this may also reveal potentially important interactions that are not evident at physiological levels of protein expression. Further, with both transgenic and knock out models the phenotype observed may be influenced by adaptive or compensatory responses to overexpression or gene inactivation.), a reasonably consistent picture of the role of {alpha}1-ARs in cardiac contractile function, particularly in pathophysiological states, and in mediating the development of pathological hypertrophy and cardiac remodelling, is beginning to emerge.


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  		Table 1 Phenotypes of genetically engineered {alpha}1-AR mouse modelsa

 

   2. Cardiac adrenergic receptors and signalling
Top
 Abstract
 1. Introduction
 2. Cardiac adrenergic receptors...
3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
 5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
 References
 
2.1 Receptor expression and control of contractility
Both contractility and growth are influenced by the sympathetic nervous system via release of the neurotransmitter, norepinephrine, and neurohormone, epinephrine, from cardiac sympathetic nerves or the adrenal medulla, respectively, to activate cardiomyocyte ARs. Each of these ARs has been classified into three subtypes: {alpha}1A,B,D, {alpha}2A/D,B,C and β1–3 (Figure 1), as detailed in several previous reviews.13–15 All ARs are seven transmembrane receptors that signal primarily via interaction with heterotrimeric G proteins.16 However, the various members of the {alpha}1-AR family couple to different cognate G proteins and activate distinct signalling pathways.16


Figure 1
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  		Figure 1 Adrenergic receptors and subtypes.

 
The hearts of most mammalian species including humans express both {alpha}1-ARs at the protein level,12,17 albeit at considerably lower levels (20%) than those of β-ARs. Interestingly, in rodents expression of {alpha}1-ARs is at least five-fold higher than in all other species including humans (Table 2).18 The {alpha}1B-subtype predominates at the protein level in rodents and, despite more marked {alpha}1A- than {alpha}1B- or {alpha}1D-AR mRNA expression in human heart,19,20 recent preliminary data suggests that expression of the {alpha}1B-AR also predominates in the left and right ventricles of both failing and non-failing human myocardium.21 In contrast to the {alpha}1A- and {alpha}1B-ARs, there is little evidence that the {alpha}1D-AR is functionally involved in regulating cardiac contractility. Although {alpha}1-ARs are expressed at similar levels in both the right and left ventricles (Table 2),18,22 little is known about potential differential expression of {alpha}1-AR subtypes in various parts of the myocardium, e.g. endocardium vs. epicardium. In rat myocardium, the relative abundance of the three subtypes is similar in all parts of the heart.22 {alpha}1-ARs are expressed by cardiomyocytes (but not by non-cardiomyocyte, such as fibroblasts), as is evident by their ability to mediate functional effects, including enhanced inotropism, with agonist activation.23


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  		Table 2 Myocardial {alpha}1-AR(adrenergic receptor) density in the right and left ventricle and as a percentage of total ARs ({alpha}1+β-ARs)

 
The β1-AR is the predominant AR regulating cardiac contractility physiologically. However, its expression falls markedly in the failing myocardium, whereas that of the {alpha}1-AR (and also the β2-AR) is maintained (Table 2).22 As a result, the proportion of {alpha}1-ARs increases in the failing heart, and in this setting is thought to play an important role in maintaining cardiac performance.13

2.2 Receptor signal transduction pathways
Both the {alpha}1A- and {alpha}1B-AR subtypes couple to the Gq family of heterotrimeric G proteins24 (Figure 2). Gq, in turn, associates with and activates phospholipase Cβ (PLCβ) family members.25 This has a number of immediate consequences. PLCβ hydrolyses inositol phospholipids, most importantly phosphatidylinositol(4,5)bisphosphate (PIP2) to generate two well-characterized second messengers: inositol(1,4,5)trisphosphate (IP3) and sn-1,2-diacylglycerol (DAG). IP3 is a regulator of intracellular Ca2+ responses whereas DAG activates some of the isomers of protein kinase C (PKC)26 as well as some of the transient receptor potential (Trp) channels (Figure 2) (see below).27 Nevertheless, it is unlikely that IP3 is a major contributor to {alpha}1A-AR responses because PLC activity and IP3-generation are low in cardiomyocytes compared with non-excitable cells. In addition, the level of expression of IP3-receptors is extremely low, approximately 1/50 of that of the ryanodine receptors that are central to beat-to-beat regulation of contractility28 and, even more importantly, IP3-receptors in ventricular myocytes are primarily localized on the nuclear membrane, seemingly distant from the site of IP3 generation.29


Figure 2
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  		Figure 2 {alpha}1-Adrenergic receptor (AR) signalling in cardiomyocytes. Agonist stimulation of {alpha}1-ARs causes activation of Gq and phospholipase Cβ (PLCβ), resulting in hydrolysis of the sarcolemmal phospholipid, phosphatidylinositol bisphosphate, PIP2, to generate inositol(1,4,5)trisphosphate (IP3), and sn-1,2-diacylglycerol (DAG). The released DAG activates conventional isoforms of protein kinase C (PKC) to initiate protein kinase cascades that culminate in altered channel activity as well as transcriptional changes. Released IP3 interacts with IP3 receptors (IP3-R), which in cardiomyocytes are localized on the peri-nuclear membrane. This causes a localized Ca2+ response resulting in activation of IP3-R-associated calmodulin-dependent protein kinase II (CAMKII). Subsequent phosphorylation of class 2 histone deacetylases 4 and 5 (HDAC4/5) facilitates their nuclear exit, and disinhibits growth-related gene transcription. PIP2 and DAG both directly regulate the activity of members of the transient receptor potential (Trp) channel family. Ca2+ entering via Trp channels activates calcineurin to initiate downstream growth signalling pathways by initially dephosphorylating the cytosolic phosphorylated form of the transcription factor, nuclear factor of activated T-cells (NFAT). Ca2+ entry through Trp channels might also act on myofilaments to enhance contractile responses. {alpha}1-AR also transactivate epithelial growth factor receptors (EGFR). Among other responses, this results in phosphoinositide 3-kinase (PI3K) activation, formation of phosphatdylinositol trisphosphate and activation of the Akt pathway, and initiation of associated downstream cell-survival signalling pathways.

 
DAG generation, on the other hand, might contribute significantly to signalling by activation of conventional PKC isoforms. Downstream effects depend on the PKC isoform involved, with PKC{delta} generally being associated with detrimental responses30 and PKC{varepsilon} with improved functional responses and cardiomyocyte survival.31 The role of these isoforms in cardiac contractile responses, however, remains controversial. A number of studies have discounted PKC involvement in Ca2+ and inotropic responses primarily on the basis of PKC inhibitor studies. Moreover, the possibility that the {alpha}1-AR, by activating PKC, can stimulate calmodulin-dependent protein kinases (CaMKII) and thereby activate the L-type calcium channels to increase Ca2+ entry, has been suggested recently.32 To further complicate this issue, it is now clear that DAG has effects that are independent of PKC activation. Important among these in heart, is the ability to activate sarcolemmal Trp channels (Figure 2).27 Trp channels are non-selective cation channels that respond to stretch PIP2 and DAG, and increase Ca2+ entry into cells in response to the emptying of IP3-sensitive Ca2+ store.33 Until recently Trp channels were not considered to be major players in cardiomyocyte responses. However, this view has been challenged recently with several Trp channels proving critical for calcineurin activation and thus for cardiomyocyte hypertrophic responses.34

In addition to generating IP3 and DAG, activation of PLC might be expected to cause reductions in PIP2, although these may be very localized and transient. PIP2 is a major regulator of ion channels and exchangers, including the repolarizing K+ channels, IKi, IKs, KUR, and KATP as well as Trp channels and the Na+/Ca2+ exchanger.35 Thus, a localized reduction in PIP2 would be expected to have major influences on cellular electrophysiology.36,37 PIP2 is also required for the generation of PIP3, a critical cardioprotective factor generated in response to activation of epithelial growth factor (EGF) receptors, among others.38 PIP2 also activates phospholipase D.39

Studies to date have not consistently identified major differences in immediate signalling responses initiated by {alpha}1A- and {alpha}1B-ARs, although there is evidence that the {alpha}1A-subtype couples to Gq-PLCβ more efficiently than the {alpha}1B-subtype.40 Our studies support this notion, as transgenic mice we developed with cardiac-targeted overexpression of {alpha}1A-ARs39 show very much higher PLC activation than mice with {alpha}1B-AR overexpression.7,41 There have also been reports that the {alpha}1A-, and not the {alpha}1B-AR subtype, activates PLC in cardiomyocytes, but these studies may have been hampered by the limited subtype selectivity of available agonists and antagonists.42

2.3 Cardiac contractility in genetically engineered models
When very highly expressed, the {alpha}1B-AR couples not only to Gq but also to Gi, thereby inhibiting Gs-mediated responses, such as β-AR-mediated increases in contractility. Thus, overexpressed wild-type (WT) {alpha}1B-ARs cause a depressed contractile response to β-AR stimulation.43 This effect was not seen in transgenic (TG) mice expressing a constitutively active (CA) {alpha}1B-AR mutant in the heart, most likely because the CA receptor was expressed at only two to three times the endogenous receptor level.44,45 Whilst differences in Gi coupling might influence responses in highly overexpressing transgenic lines, there is no reason to suggest that at physiological expression levels the {alpha}1B-AR interacts with Gi. It is, thus, unlikely that signalling pathways downstream of Gi are important for {alpha}1-AR effects on cardiac function. In contrast to these {alpha}1B-AR responses, even when very highly overexpressed (170-fold), the {alpha}1A-AR does not appear to interact with Gi.7

{alpha}1-ARs in cardiomyocytes also transactivate the EGF receptor and much of the downstream signalling depends on this response,46 especially those pathways associated with cell survival (Figure 2).47 It is currently not known which {alpha}1-AR subtype mediates this response. Transactivation of EGF receptors appears to be common to all Gq-coupled receptors, since receptors for angiotensin II (AT1), endothelin,48 and purinergic agonists46 all produce this response and, furthermore, overexpressing G{alpha}q can mimic the response47. Thus it is likely that all {alpha}1-AR subtypes can transactivate EGF receptors, since all activate Gq.

While Gq involvement in EGF receptor transactivation has been well established, it is unclear if PLCβ activation is also part of this response. Originally EGF receptor transactivation was thought to be critical for cellular growth responses,49 but recent studies have argued that EGF receptors initiate cell survival responses rather than growth per se.47 The fact that cell survival is necessary for cellular growth further complicates this issue. Our studies, in which {alpha}1-ARs were considerably overexpressed, as well as those of other laboratories, have found that heightened {alpha}1B-, but not {alpha}1A-AR activity, predisposes to hypertrophy.7,45,50 In contrast, recent studies in which {alpha}1-ARs were selectively inactivated indicate that the {alpha}1A-, but not the {alpha}1B-AR, is critical for cardiomyocyte survival.51 As activation of ERK1/2 is generally considered part of cell survival signalling, this finding contradicts the notion that the {alpha}1B-AR is solely responsible for this response.


   3. Involvement of {alpha}1-adrenergic receptors in contractility, cardiac growth, hypertrophy, and remodelling
Top
 Abstract
 1. Introduction
 2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
4. Ischaemia and reperfusion
 5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
 References
 
3.1 Hypertrophy and remodelling
Under physiological conditions adrenergic responses are mediated predominately by the β1-AR acting via Gs and the adenylyl cyclase-protein kinase A pathway to acutely increase the rate and force of contraction and, longer-term, to influence cardiac size through hypertrophic growth.52 The β1-AR recognizes the neurotransmitter, norepinephrine, with higher affinity than the β2-AR and, in humans, the former mediates not only pathological hypertrophy, evident by induction of foetal gene expression, but also apoptosis, tachycardia-associated ischaemia, and myocardial damage.53 Cardiomyocytes express {alpha}1- but not {alpha}2-ARs. Although {alpha}1-ARs are not generally considered to be major regulators of cardiac contractile function under physiological conditions (for a more detailed consideration of the physiological effects of {alpha}1A-AR activation, see12,17), as indicated earlier, they are thought to exert more influence under pathological conditions, such as ischaemia and heart failure when β1-AR signalling is compromised.

Cardiac remodelling is a dynamic process in which the heart undergoes structural changes, including changes in chamber size and shape, myocardial mass and interstitial structure, in response to haemodynamic overload or myocardial injury. In general, these changes contribute importantly to the development of systolic and diastolic contractile dysfunction.11 In addition to morphological changes, cardiac remodelling also involves changes at the cellular and molecular levels that reflect the underlying mechanisms – so called molecular or electrophysiological remodelling. Although remodelling may initially be adaptive because the change in LV geometry normalizes wall stress,54,55 it gradually becomes maladaptive and results in cardiac decompensation.56 Minimizing or reversing remodelling, therefore, is now regarded as an important therapeutic goal in the prevention or treatment of congestive heart failure.11

3.2 {alpha}1B-Adrenergic receptor models
As detailed later, mouse models of altered cardiac {alpha}1-AR expression show significant cardiac remodelling that appears to be subtype-specific. Thus, when overexpressed in mice under the control of a cardiac-specific ({alpha}-MHC) promoter that induces ventricular expression starting soon after birth, neither the {alpha}1A nor {alpha}1B-AR causes significant hypertrophy, as would be evidenced by an increase in heart weight to body weight ratio or in cardiomyocyte size.7,41 Rather, cardiac-restricted overexpression of the WT {alpha}1B-AR (>40-fold) resulted in the development of dilated cardiomyopathy (Table 3), manifested by a progressive increase in LV chamber size by 80% from 3 to 9 months of age. Systolic dysfunction, although less pronounced, was also present and the animals progressed to develop heart failure and to die prematurely.43,57 However, neither LV nor heart weight increased until heart failure was established. In contrast, not only was hypertrophy not observed in {alpha}1A-AR transgenic mice despite four- to 170-fold receptor overexpression, but the animals with more marked overexpression (66- to 170-fold) displayed hypercontractile cardiac function.7


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  		Table 3 Comparative cardiac phenotypes observed when transgenic mice with cardiac-restricted {alpha}1A-AR (adrenergic receptors) ({alpha}1A-TG) or {alpha}1B-AR ({alpha}1A-TG) overexpression were subjected to pressure overload, catecholamine stimulation or myocardial infarction. Changes are relative to respective wild-type (WT) littermates

 
Given these findings, particularly the lack of hypertrophy despite >40-fold {alpha}-MHC promoter-mediated overexpression of the WT {alpha}1B-AR, it is surprising that modest but significant hypertrophy was observed in transgenic mice with only two-fold overexpression of the WT {alpha}1B-AR under the control of an isogenic (endogenous) promoter.58 With this promoter, receptor overexpression is not confined to the heart but is observed in all tissues that express the {alpha}1B-AR, including the brain. This makes interpretation of these findings difficult because these animals also displayed neurodegeneration with impaired sympathetic output, as reflected by reduced catecholamine levels.58 Interestingly, in these animals cardiac output was markedly reduced (by 57%) but blood pressure was unaltered, suggesting that counter-regulatory mechanisms independent of the sympathetic nervous system, such as activation of the renin angiotensin system, must be operative to maintain peripheral vascular resistance. Thus, it is plausible that the cardiac hypertrophy in this transgenic model is unrelated to cardiac {alpha}1B-AR overexpression, but rather is due to other factors, such as excessive angiotensin II acting on cardiac AT1 receptors.

In contrast to these findings with the WT {alpha}1B-AR transgenic models, genetically engineered mice overexpressing CA mutants of this receptor displayed marked hypertrophy, whether receptor expression was under the control of an isogenic promoter or the {alpha}-MHC promoter.58,59 Although the degree of overexpression was only two- to three-fold with both promoters, development of hypertrophy is not surprising, given that CA {alpha}1B-ARs produce sustained receptor signalling because of their constitutive activation, with activation and signalling being further augmented by the fact that these mutants also have a marked increase in their affinity for catecholamines.60,61

3.3 {alpha}1A-Adrenergic receptors models
An isogenic promoter has also been used to develop transgenic mice with two- to three-fold overexpression of a CA {alpha}1A-AR. These animals, in which receptor overexpression is not confined to the heart but is also observed in other tissue, do not display altered autonomic activity or contractile function. However, they display enhanced restoration of contractile function following an ischaemic insult, indicating that cardiac {alpha}1A-AR activity can inherently precondition the myocardium against ischaemic injury, via a mechanism that is apparently PKC-independent.62

3.4 Pressure overload and receptor activation in {alpha}1B-adrenergic receptor models
Despite minimal effects on physiological heart growth, increased {alpha}1B-AR activity resulting from overexpression of a CA mutant in the heart substantially amplified the hypertrophic response to pressure overload, and also resulted in heart failure and premature death.7,45,50 The enhanced hypertrophic response was associated with increased cardiomyocyte size as well as increased fibrosis. Thus, activated {alpha}1B-AR signalling exacerbated the response to pressure overload, leading to more severe cardiac remodelling and dysfunction.

Similar findings were observed in mice with cardiac-restricted overexpression of the WT {alpha}1B-AR given an infusion of the {alpha}1-AR agonist, phenylephrine.63 These animals also exhibited poor survival, markedly exaggerated cardiac hypertrophy, myocardial fibrosis, markedly suppressed sarcoendoplasmic reticular Ca2+ ATPase (SERCA) gene expression, and suppressed LV function (Table 3). In addition, {alpha}1-AR mediated downregulation and activation of β-AR kinase-1 (βARK1) were evident following the induction of hypertrophy by treatment of WT {alpha}1B-AR overexpressing mice with the {alpha}1B-AR agonist, phenylephrine.63 Thus, increased activity of the {alpha}1B-AR, while not causing substantial hypertrophy in its own right, nonetheless positively modulates the hypertrophic response to other effectors.

3.5 Pressure overload in {alpha}1A-adrenergic receptor models
In contrast to the {alpha}1B-AR, cardiac-restricted overexpression of the {alpha}1A-AR in mice increases systolic contractile function, but does not result in increased heart or cardiomyocyte size, neither enhances nor diminishes pressure overload hypertrophy, and does not hasten the development of heart failure in response to chronic pressure overload or myocardial infarction.7,50 Moreover, in this {alpha}1A-transgenic model there is no evidence of the promiscuous crosstalk with β-AR signalling pathways that is observed with overexpression of the WT {alpha}1B-AR.41,43 In fact, in animals with 66-fold receptor overexpression, heightened {alpha}1A-AR activity improves survival,50 although with very marked overexpression (170-fold) cardiac fibrosis is evident and survival is reduced.64 Thus, the {alpha}1A-AR is neither an initiator nor a modulator of cardiac hypertrophy, although an effect on physiological hypertrophy has not been studied and therefore cannot be entirely excluded.

Indeed, it is of interest, that overexpression of the {alpha}1A-AR, under the control of the {alpha}-MHC promoter, abrogates cardiac remodelling in response to either thoracic aorta constriction (TAC)-induced pressure overload or myocardial infarction (Figure 3).50,65 Thus, following TAC the hypercontractile phenotype associated with {alpha}1A-AR overexpression persists despite chronic pressure overload and comparable degrees of hypertrophy, but increases in LV chamber size are significantly less than in non-transgenic littermates (NTLs) (Figure 3).50 In addition, the extent of increase in myocardial collagen is comparable with pressure overload but more severe in the non-infarcted myocardium of the {alpha}1A-AR overexpressing animal compared with their NTLs.50,65


Figure 3
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  		Figure 3 (A) Echocardiographic M-mode traces from transgenic mice with cardiac-restricted overexpression of the {alpha}1A-adrenergic receptor (TG) or their non-transgenic littermates (NTLs) subjected to sham-operation (SH), transverse aorta constriction (TAC) for 12 weeks (upper panels) or myocardial infarction (MI) for a period of 15 weeks (lower panels). In both heart disease models, the NTLs showed a more pronounced increase in left ventricular dimensions (left panels of representative M-mode echocardiographic images) than the TG mice. Note that the infarcted are akinetic (arrowhead). (B) Left ventricular function estimated from fractional shortening measured at the end of the study periods was significantly better as compared with that of the NTLs. *P < 0.01 vs. respective SH; {dagger}P < 0.01 vs. respective NTL. Data are adapted from references50,65 with permission.

 
These results are surprising for several reasons. First, pharmacological studies of {alpha}1-AR activation in neonatal rat cardiomyocytes have implicated the {alpha}1A as the subtype mediating hypertrophy,66 albeit that the agonists/antagonists used to define this subtype were poorly selective.14 Secondly, studies from our laboratory demonstrated increased expression of the {alpha}1A-AR in response to {alpha}1-AR agonist-treatment of isolated cardiomyocytes; a finding also observed by others in the hearts of adult rats with pressure overload hypertrophy.67,68 These findings further added weight to the concept that hypertrophy was most likely mediated primarily by the {alpha}1A-AR subtype. Thirdly, downstream signalling pathways have generally been considered similar for the two {alpha}1-AR subtypes.69 Fourthly, both the {alpha}1A- and {alpha}1B-ARs activate Gq, a well-established initiator of cardiac growth in vivo and in isolated cardiomyocytes.70

One caveat to these {alpha}1A-AR transgenic and knockout studies, of course, is that the hypertrophic mechanisms may differ in the mouse compared with the rat – an issue of potential clinical importance, given that the levels of {alpha}1-AR expression in human heart are similar to those in the mouse, but markedly less than in the rat (Table 2). To address this issue, we recently developed a transgenic rat model with cardiac-restricted overexpression of the {alpha}1A-AR. However, despite overexpression to levels 40-fold higher than in the hearts of NTLs, cardiac hypertrophy was again not observed (Yu ZY, Iismaa S, Tan JC, Maraniec T., MacMahon AC, Sharp D., Kesteven SH, Xiao XH, Reichelt ME, Wang Z, Wiliamson D., Graham RM, Feneley MP, unpublished results).

3.6 {alpha}1-Adrenergic receptors subtypes and cardiac growth
The marked selectivity of cardiac growth responses for the {alpha}1B- over the {alpha}1A-AR subtype indicates either that some critical factor is selectively regulated by the {alpha}1B-AR or, alternatively, that the {alpha}1A-AR activates growth inhibitory pathways. This latter explanation seems unlikely because the degree of hypertrophy seen in the {alpha}1A-AR overexpressing animals was identical to, not less than, that in NTLs after pressure overload.50 Thus, it is likely that some factor critical for hypertrophy is activated by the {alpha}1B-, but not by the {alpha}1A-subtype. Possible candidates here include EGF receptor transactivation, Trp channel/calcineurin activation or IP3-mediated transcriptional responses.29

In agreement with studies in transgenic mice, hearts from animals in which genes encoding both the {alpha}1A- and the {alpha}1B-AR genes have been deleted were smaller than those of their NTLs, albeit that deletion of either the {alpha}1A-AR or {alpha}1B-AR alone did not affect heart size; the latter finding suggesting compensation by the remaining receptor. Nonetheless, this implies at least a permissive role for these receptors in post-natal physiological hypertrophy.71 The double knockout animals also showed exercise intolerance, further supporting this view. However, pathological hypertrophy induced by pressure overload was not altered in the double knockout mice, providing evidence for differences in the signalling pathways mediating physiological vs. pathological hypertrophy, as has been suggested by other studies.72,73 This also supports studies showing that endogenous {alpha}1B-ARs are not critical for the development of hypertrophy in vivo,74 even though heightened {alpha}1B-AR activity can exacerbate the response.

Thus, pathological hypertrophy associated with pressure overload is influenced by {alpha}1B-ARs but not {alpha}1A-ARs, whereas both subtypes modulate the physiological hypertrophy associated with post-natal growth.


   4. Ischaemia and reperfusion
Top
 Abstract
 1. Introduction
 2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
 References
 
4.1 Effects on infarct size and function
In the case of recovery from ischaemic injury, studies using transgenic mice with {alpha}1A- and {alpha}1B-AR expression under either their endogenous promoters or an {alpha}-MHC promoter have provided essentially similar insights. Heightened {alpha}1B-AR activity, achieved by overexpressing a CA mutant did not alter tolerance to myocardial ischaemic injury, as determined by infarct size or functional recovery.44,62 This might imply a failure of the {alpha}1B-AR to precondition the heart albeit that there is evidence from studies of isolated cardiomyocytes that activation of this subtype alleviates ischaemia-reperfusion injury by limiting mitochondrial Ca2+ overload.75

Increased {alpha}1A-AR activity, improves functional recovery from ischaemia-reperfusion in the short term62 and, longer-term, protects against progression to heart failure.65 As seen in the TAC model,50 enhanced baseline contractility in our mouse model of cardiac restricted {alpha}1A-AR overexpression is also most likely the cause of increased tolerance to ischaemia.65 However, in the study of Rorabaugh et al.62 involving expression of a CA {alpha}1A-AR mutant under control of its isogenic promoter, the hearts displayed depressed contractile function under both basal and β-AR stimulated conditions. Thus, any post-ischaemic protection observed in our cardiac {alpha}1A-overexpressors may reflect an acute preconditioning mechanism activated by {alpha}1A-AR signalling.62 Indeed, there is evidence that {alpha}1-ARs play an important role in both the first (short-term) and second windows (long-term) of preconditioning.62,76

4.2 Ischaemia/reperfusion
We have shown that reperfusion of rat or mouse hearts after brief periods of ischaemia causes the generation of large amounts of IP3, which appears to be essential for the development of arrhythmias in early reperfusion.77,78 Overexpression of either the {alpha}1A- or {alpha}1B-AR increases PLC-mediated responses to {alpha}1-AR agonists, although the {alpha}1A-AR overexpressing animals show much stronger enhancement. In contrast to their NTLs, neither strain appears to produce large amounts of IP3 in response to stimulation under physiological or normoxic conditions.79 While increasing PLC responses under normoxic conditions, expression of a CA {alpha}1B-AR mutant actually prevents PLC activation by norepinephrine during post-ischaemic reperfusion.79 These CA receptors also protect against reperfusion arrhythmias, ventricular tachycardia, and ectopic beats in this mouse strain. This indicates that the {alpha}1B-AR protects the myocardium against reperfusion arrhythmias, presumably by a mechanism similar to ischaemic preconditioning. If this is the case, then this preconditioning effect appears to be selective for arrhythmogenic responses because, unlike {alpha}1A-AR overexpression, overexpression of a CA {alpha}1B-AR did not reduce infarct size or improve functional recovery after brief ischaemia.44,62

Interestingly, overexpression of {alpha}1A-ARs also prevents IP3 generation in early post-ischaemic reperfusion. Unfortunately, the background strain of mice used for generation of the {alpha}1A-AR overexpressing lines was resistant to reperfusion arrhythmias. Thus, an anti-arrhythmic effect of heightened {alpha}1A-AR activity could not be evaluated in these mice. Mice with cardiac-restricted {alpha}1A-AR overexpression also showed improved functional recovery, but this is unlikely to be directly related to the loss of IP3 generation, given that no such improvement was seen in animals with overexpression of a CA {alpha}1B-AR, despite similar lack of an IP3 response.79


   5. Involvement of {alpha}1A-adrenergic receptors in human heart function
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 2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
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6. Conclusion
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5.1 Heart failure and hypertension
Blockade of {alpha}1-ARs has been a widely used therapeutic approach for the treatment of hypertension and congestive heart failure for many years.80,81 However, only recently has the potential for this therapy to impair cardiac performance by blockade of cardiac {alpha}1-AR drive, come to light. Evidence dating back to the 1960s implicated acute loss of adrenergic drive resulting from the use of the sympatholytic agent, guanethidine, in the exacerbation of congestive heart failure symptoms.82 However, it was unclear if this was due to impaired {alpha}- or β-AR activation or both. Moreover, at that time insights into the control of cardiac contractility by sympathetic mechanisms, particularly via {alpha}-ARs, was still limited. Subsequently, non-selective {alpha}-AR blockers, such as phentolamine and phenoxybenzamine were used in the treatment of hypertension and heart failure. Unfortunately, these agents blocked not only post-junctional vasoconstrictor {alpha}1-ARs, but also pre-junctional {alpha}2-ARs that inhibit sympathetic neurotransmitter release. As a result, reductions in peripheral resistance and blood pressure by these treatments initiate counter-regulatory increases in renin release and heart rate, as well as fluid retention.81 Prazosin and later trimazosin, {alpha}1-AR-selective agents, proved to be much more effective antihypertensive agents with little activation of counter-regulatory mechanisms.83 In the setting of heart failure, however, although {alpha}1-AR-selective blockers initially produced a useful reduction in afterload by decreasing peripheral resistance, longer-term patients developed tolerance to this salutary haemodynamic effect, albeit inhibition of vasoconstrictor tone was still evident when sympathetic activity was increased by exercise.81 This lead to the suggestion that their use be restricted to patients with more severe heart failure that basally have markedly increased sympathetic tone and, thus, may be more responsive to selective {alpha}1-AR-blockade than those with mild heart failure.81

5.2 Cardioprotection
Evidence for a potential cardioprotective role of {alpha}1-ARs, however, came to light only with more recent antihypertensive trials, such as the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) study.84,85 In this large clinical trial comparing the effects of the {alpha}1-AR-selective blocker, doxazosin, with the diuretic, chlorthalidone, the doxazosin arm was discontinued prematurely due to doubling in the incidence of heart failure.84 In addition, in the vasodilator-heart failure trials (V-HeFT), unlike other vasodilators, the {alpha}1-AR-selective blocker, prazosin, did not improve survival.86 High doses of both prazosin and doxazosin have also been found from in vitro studies to cause apoptosis by a mechanism independent of {alpha}1-AR blockade.87 Thus, the negative effects of these agents in these antihypertensive and heart failure trials may at least in part be non-specific and, thus, {alpha}1AAR-independent. Nonetheless, these clinical trial findings are entirely in keeping with the animal studies discussed earlier, indicating that activation of cardiac {alpha}1-ARs, particularly the {alpha}1A-AR subtype, produces salutary cardiac effects, including the provision of useful contractile support in the setting of ischemia65 or pressure overload,50 thereby preventing a maladaptive response to increased workload,88 can protect against ischaemic injury,62 and is critical for protection against apoptosis89 and for cardiomyocyte survival.51

5.3 Clinical trials and pharmacological considerations
The findings of the ALLHAT84,85 and V-HeFT trials are, however, in apparent contradiction to those of clinical trials of heart failure treatment showing enhanced efficacy of cardevilol, an agent that blocks not only β- but also {alpha}1-AR, over agents, such as metoprolol, that lack {alpha}1-AR blocking activity. Thus, one might ask: why is {alpha}1-AR blockade deleterious in some studies but seemingly beneficial in other? Resolution of this conundrum is apparent, we believe, from a careful consideration of the pharmacology of carvedilol. This reveals that its {alpha}1-blocking activity is weak (only 1/10 of its β-blocking effects90), and with long-term use its {alpha}1-AR blocking effects do not persist or contribute to its haemodynamic actions.91,92 Further, the affinity of the {alpha}1A-AR (pKi 7.9) for carvedilol is considerably lower than that of the {alpha}1B-AR (pKi 8.9).93 Thus, with chronic dosing its {alpha}1-AR blocking activity, particularly of the subtype most relevant to the regulation of contractile function and cardiomyocyte survival – the {alpha}1A-AR – is likely irrelevant. Similarly, Bristow et al.53 have argued that the greater efficacy of carvedilol in heart failure, compared with β1-blocking drugs, is not due to its ability to block both β1- and β2-ARs. Rather, it is possible that carvedilol’s unique efficacy is attributable to its non-AR blocking actions, such as its anti-arrhythmic activity,94–96 and its antioxidative and anti-apoptotic properties that may be involved in limiting free radical damage of vascular endothelium, as well as in reducing myocardial injury and infarct size after ischaemia-reperfusion.97–101


   6. Conclusion
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 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
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 6. Conclusion
Funding
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In conclusion, it is likely that continued activation of cardiomyocyte {alpha}1-ARs plays a hitherto under-appreciated role in maintaining cardiac performance and in preventing maladaptive cardiac remodelling, particularly in the face of increased pressure overload. Indeed, our finding of reduced heart failure after myocardial infarction or the induction of pressure overload in transgenic animals with cardiac-restricted overexpression of the {alpha}1A-AR, suggests that strategies to selectively activate only cardiomyocyte {alpha}1A-ARs might be useful adjunctive therapy in a variety of clinical settings, where maintenance of cardiac performance is critical for preventing progression to heart failure.

Conflict of interest: All authors declare that they have no conflicts to declare, either real or perceived.


   Funding
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 Abstract
 1. Introduction
 2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
 5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
References
 
Studies from the authors’ laboratories were supported in part by National Health and Medical Research Council, Australia. Grants nos: 225108 (X.-J.D.); 317801, 317802, and 268921 (E.A.W.); and 354400 (R.M.G.), and fellowship nos: 317808 (X.-J.D.) and 317803 (E.A.W.).


   References
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 1. Introduction
 2. Cardiac adrenergic receptors...
 3. Involvement of {alpha}1...
 4. Ischaemia and reperfusion
 5. Involvement of {alpha}1A...
 6. Conclusion
 Funding
 References
 

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