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<em>and#946;</em>-adrenergic System and Cardiac Physiology and Pathophysiology | OMICS International
ISSN: 2329-6607
Cardiovascular Pharmacology: Open Access
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β-adrenergic System and Cardiac Physiology and Pathophysiology

Ying Li1, Xiaoying Zhang2 Yi-zhi Peng1 and Xiongwen Chen2*

1The Third Military Medical University, Chongqing, China

2Cardiovascular Research Center & Department of Physiology, Temple University School of Medicine, USA

*Corresponding Author:
Xiongwen Chen
Cardiovascular Research Center & Department of Physiology
Temple University School of Medicine, USA
Tel: +215-707-3542
Fax: 215-707-5737
E-mail: [email protected]

Received date: November 20, 2012; Accepted date: November 21, 2012; Published date: November 23, 2012

Citation: Li Y, Zhang X, Chen X (2012) ß-adrenergic System and Cardiac Physiology and Pathophysiology. Cardiol Pharmacol 1:101. doi:10.4172/2329-6607.1000101

Copyright: © 2012 Li Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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The heart is under constant regulation to maintain cardiac output to meet different needs of tissue perfusion under different conditions. Acutely, the regulation is mediated by the sympathetic/ β-adrenergic system (SAS) and the vagal/parasympathetic system. The SAS system is activated to exert positive chronotropic, inotropic, and lusitropic effects on the heart when a greater need of cardiac output is imposed. Chronic activation of SAS contributes to the development of cardiac dysfunction and arrhythmias. Although the roles of the SAS system in cardiac physiology and pathophysiology have been studied for decades, many questions remain and new discoveries have been made during the past decade.

SAS and Cardiac Function Regulation in Normal Heart Physiology

Adrenergic agonists, such as epinephrines and norepinephrines are released when the SAS is excited and then bind to the β-adrenergic receptors (β-ARs, including β1 (75%), β2 (25%), the existence of β3-AR in the heart is still in debate). The binding of β-AR agonists dissociates Gβγ from Gαs, which in turn activates the adenylyl cyclase (AC) that catalyzes the production of cyclic-AMP (cAMP) from ATP. Subsequently cAMP activates PKA that phosphorylates multiple targets in cardiac myocytes: the L-type calcium (Ca2+) channel (LTCC), the phospholamban (PLB), the ryanodine receptor (RyR), and troponin I, causing the increase in cardiac contractility (inotropy) and relaxation rate (lusitropy) [1]. In addition, cAMP directly [2] or indirectly via PKA enhances pace making currents in the heart to increased heart rate (chronotropy) [3]. PKA also phosphorylates metabolic enzymes (e.g., phosphorylase kinase) to increase the metabolic rate to match the enhanced demand of energy of the stimulated heart. Lastly, activated PKA is able to regulate gene expression via the activation of cAMP response element binding (CREB) protein, a transcription factor and other cAMP response element modulators (e.g., CREM).

The β-adrenergic signaling can be shut off once the SAS system is not excited by multiple mechanisms: catecholamines in the extracellular milieu can be decreased by metabolism or reuptake by norepinephrine transporter on the sympathetic nerve ends [4]; the β-ARs can be desensitized by PKA or G-protein coupled receptor kinase (GRK)- dependent phosphorylation and internalization [5]. Intracellular cAMP is returned to normal level by cAMP hydrolysis by phosphodiesterases (mainly PDE3 and PDE4) [6]. GRK2 is able to phosphorylate both β1-AR and β2-AR, followed by the binding of arrestin [7], which is able to recruit PDE4 to further limit local cAMP increase [8]. The internalization of β2-AR requires PI3K association with the agonistbound β2-AR [9]. At last, the PKA-mediated phosphorylation is removed from its target molecules by protein phosphatases (PP1 and PP2A in the heart).

It had been thought β-AR signaling was well studied, but recently it has been demonstrated that cAMP/PKA signaling is far more complex than what we have conceived:

1. β2-AR dually couples to both Gs and Gi [10] and the effects of β2- AR activation can be switched from Gs-PKA to Gi [11] to activate PI3K and Akt, which exerts anti apoptotic effect opposing the proapoptotic effect of β1-AR [12]. In addition, β2-AR stimulation causes ERK1/2 phosphorylation in a Gi-dependent manner. The σ®-AR also couples to and regulates Na+/H+ exchanger [13]. 2, the cAMP/PKA signaling is compartmented spatially by a couple of mechanisms: 1) the adrenergic receptors locate at specific membrane domains such as caveoli, where ACs, PKA and their target molecules are also concentrated [14].

2. A-protein anchoring proteins (AKAPs) serve as a scaffolding protein to organize a signalosomes comprised of β-AR, AC, PKA, PDEs and LTCC etc [15]. PDEs in close vicinity of AC and PKA limit the local concentration of cAMP.

3. There is another cAMP sensor, exchange protein directly activated by cAMP (EPAC), in the heart. EPAC1 is highly expressed in the heart but EPAC2 is not [16]. Both PKA and EPAC have similar affinities to cAMP, indicating that EPAC may play a role in normal physiology [17]. EPAC1 seems to play a role in mediating β-AR stimulated increase in myocyte Ca2+ transients and contractions in a PLCε-dependent manner [18]. However, this finding cannot be always repeated and needs further investigation [19]. EPAC activates while PKA suppresses PKB/Akt to affect myocyte survival [20]. Like PKA, EPAC signaling can be spatially and temporally regulated by PDE and AKAP [21]. Both EPAC and PKA promote PDE4D3 activity to attenuate cAMP signaling [22].

4. The β-AR/AC/cAMP/PKA pathway interacts with many other signaling pathways. The activation of β-ARs is also able to activate Ca2+/calmodulin-dependent kinases II (CaMKII) [23] through PKAdependent mechanism [23] or independent mechanisms [24,25].

SAS Signaling in Cardiac Pathophysiology

Chronic activation of the SAS is a cause for the progression of heart failure (HF) [26,27]. The level of the activation of the SAS system evaluated by the increased blood catecholamine concentration [28] or the nerve activities [29] is closely correlating with the severity of HF [26]. It is believed that enhanced SAS activity is beneficial to maintain the normal hemodynamics initially but gradually causes adverse molecular, cellular and structural remodeling to further weaken the heart [30]. Chronic adrenergic stimulation (e.g., chronic isoproterenol infusion [31,32], sustained high intracellular cAMP concentration [33], and over expression of β-ARs [34] or Gαs [35] or PKA [36]) of the heart in animal models leads to HF. Currently, myocyte death caused by high adrenergic drive is linked to intracellular Ca2+ overload and the activation of CaM K II [37-41]. CREB activation by increased intracellular cAMP/PKA activity is involved in cardiac myocyte hypertrophy and apoptosis [42]. Inhibition of CREB reduces cardiac myocyte hypertrophy but promotes cardiomyocyte apoptosis [42]. EPAC activated by elevated cAMP is also able to induced cardiac myocyte hypertrophy via Rac-dependent activation of the calcineurin/ NFAT pathway in cardiac myocytes [43].

β1-AR density decreases in failing hearts. β2-AR maintains its density but is uncoupled from Gs, probably due to increased GRK2 and GRK5 activities in HF [44]. Concomitantly, the expression Gi is increased in failing hearts [45] and thus uncouples Gαs from β2-AR. These changes decrease β-AR stimulation induced cAMP production and eventually the adrenergic responsiveness and exercise tolerance in failing hearts [46]. Currently it has been conceived that the decreased or blunted β-adrenergic response is a protective mechanism to avoid some detrimental effects (e.g., myocyte death) of heightened catecholamines because β-blockers is able to further protect failing hearts [47]. There is polymorphism of β-ARs which could affect the progression of heart disease [48]. In the failing human heart, the coupling of ACs to β-AR is decreased in HF [49,50].

Since chronic SAS activation plays such an important role in HF progression, the blockade of β-ARs has been developed into a standard therapy according to the Guidelines of ACC/AHA [51] and HFSA [52]. Large randomized controlled clinical trials with bisoprolol [53], metoprolol succinate [53] and carvedilol [54] have provided clear evidence of reducing mortality and morbidity and improving CHF symptoms by β-blockers. The efficacy of β-blockers is affected by the etiology (more effective in dilated cardiomyopathy than in ischemic cardiomyopathy [55]) with large patient-to-patient variation probably because of the polymorphism of β-ARs [48]. The cellular and molecular mechanisms of β-blockers are not clearly understood but could be related to lowering the heart rate [56] and normalizing adrenergic responsiveness by restoring β-AR density [57], reducing Gi expression [58] and the early transient activation of GRK2 [59]. On the other hand, β-adrenergic agonists, PDE inhibitors and AC agonists can only be used as acute positive inotropic drugs for stabilizing hemodynamics [60]. However, administration of PDE inhibitors for a long term in HF patients increases mortality and morbidity [61,62]. Since β2-AR/Gi activation protects myocytes from apoptosis through a PI3K/AKT-dependent mechanism, the co-application of β1-blockers with β2-agonist has been explored and shown predicted protection effect in HF animal models [63,64]. In addition, Gi activation exerts anti arrhythmia effect [65,66]. Despite that, to date, there is no clinical trial adopting this strategy because early clinical trials with a β2-AR agonist, fenoterol, were not successful. GRK inhibition is also studied for potential treatment of HF aiming to restore the blunted adrenergic response [67,68]. Inhibiting GRK2 [69,70] or disrupting PK3K/GRK2 interaction with βARKct has been shown to prolong survival, attenuate cardiac hypertrophy and mitigates heart failure development [71] in animal models of heart failure [72-74]. Most recently, we have shown that PKA inhibition by PKI could be a novel therapy for HF treatment [75].


Since the SAS plays such important roles in cardiac physiology and pathophysiology, further studies to elucidate the novel aspects of this system and targeting novel molecules for heart disease prevention and treatment are warranted.


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