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Cholinergic Activity As a New Target in Diseases of the Heart

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Cholinergic Activity As a New Target in Diseases of the Heart Cholinergic Activity as a New Target in Diseases of the Heart Ashbeel Roy,1,2 Silvia Guatimosim,3 Vania F Prado,1,2,4 Robert Gros,1,2,5 and Marco A M Prado1,2,4 1Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada; 2Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada; 3Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; 4Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario, Canada; and 5Department of Medicine, University of Western Ontario, London, Ontario, Canada The autonomic nervous system is an important modulator of cardiac signaling in both health and disease. In fact, the signifi- cance of altered parasympathetic tone in cardiac disease has recently come to the forefront. Both neuronal and nonneuronal cholinergic signaling likely play a physiological role, since modulating acetylcholine (ACh) signaling from neurons or cardiomy- ocytes appears to have significant consequences in both health and disease. Notably, many of these effects are solely due to changes in cholinergic signaling, without altered sympathetic drive, which is known to have significant adverse effects in disease states. As such, it is likely that enhanced ACh-mediated signaling not only has direct positive effects on cardiomyocytes, but it also offsets the negative effects of hyperadrenergic tone. In this review, we discuss recent studies that implicate ACh as a major regu- lator of cardiac remodeling and provide support for the notion that enhancing cholinergic signaling in human patients with car- diac disease can reduce morbidity and mortality. These recent results support the idea of developing large clinical trials of strat- egies to increase cholinergic tone, either by stimulating the vagus or by increased availability of Ach, in heart failure. Online address: http://www.molmed.org doi: 10.2119/molmed.2014.00125 OVERVIEW Genesis of ACh depends on the actions presynaptic nerve terminal (5), where it Acetylcholine (ACh) is an ancient sig- of the enzyme choline acetyltransferase can be used to synthesize ACh and main- naling molecule that regulates many (ChAT) (1), which converts free choline tain its sustained release. No other physiological functions both in the cen- and acetyl-CoA into ACh, a process first choline transporter can replace CHT1 in tral and peripheral nervous system. In described by Nachmansohn and cholinergic nerve endings, since its ge- the periphery, ACh is the major chemical Machado (2). ChAT is in kinetic excess in netic deletion leads to death shortly after neurotransmitter, regulating both nerve terminals; therefore, minor reduc- birth because of respiratory failure (6). parasympathetic and sympathetic tone. tions in ChAT activity have negligible The secretion of ACh into the extracel- Importantly, the autonomic nervous sys- impact on ACh content and release (3). lular environment depends on its packag- tem regulates the function of several dif- ACh synthesis is exquisitely coupled to ing into exocytic vesicles via the vesicular ferent organ systems via activation of the high-affinity choline transporter acetylcholine transporter (VAChT) (7). very specific pathways. However, for the (CHT1), which serves as the rate- limiting VAChT is a 12-transmembrane domain purpose of this review, which focuses on step for ACh production (4). This step is protein that uses the electrochemical gra- its effects in the cardiovascular system, because of the importance of CHT1 in dient of a proton ATPase to store ACh in parasympathetic and sympathetic tone regulating the transport of sufficient synaptic vesicles (7). Elimination of the will refer to autonomic efferent outflow amounts of free choline from the extra- VAChT gene abolishes stimulated ACh re- to the heart. cellular environment into the cholinergic lease (8). In addition, decreased expres- sion levels of VAChT lead to proportional decreases in ACh release (9). On the other hand, overexpression of VAChT in imma- Address correspondence to Marco A M Prado, Robarts Research Institute, 100 Perth ture Xenopus neurons leads to increased Drive, London, Ontario, N6A 5B7, Canada. Phone: 519-931-5777, x24888; Fax: 519-931- synaptic responses (10). Furthermore, 5789; E-mail: [email protected]. overexpression of VAChT in mice has Submitted June 27, 2014; Accepted for publication September 9, 2014; Epub been shown to increase ACh release (www.molmed.org) ahead of print September 10, 2014. (11,12), improve physical fitness and cause abnormalities in cognitive behavior (11). Hence, VAChT expression is unique in its ability to regulate ACh release. MOL MED 20:527-537, 2014 | ROY ET AL. | 527 ACETYLCHOLINE IN THE HEART The parasympathetic nervous system ing via the M3 muscarinic receptor in the ing (34–36), although it acts on the latter acts through the vagus nerves, which heart is coupled with Gq-mediated acti- with a lower potency and shows Gq se- mainly innervate the atria of the heart, vation of the phospholipase C (PLC)/IP3 lectivity (37). In addition, RGS2 has pre- with some sparse ventricular innervation pathway. Furthermore, M3 receptors viously been shown to reduce adenylyl (13), and plays a crucial role in regulat- were also shown to mediate inotropic cyclase activity downstream of Gs signal- ing several aspects of cardiac physiology. signaling in the atria (25). The biphasic ing (38). Importantly, RGS2 can inhibit Cholinergic signaling leads to a reduc- inotropic response observed in isolated hypertrophy in response to β-adrenergic tion in heart rate, the contractile forces of atria has been attributed to both M2 and stimulation (39), an effect that may par- the atria and the conduction velocity of M3 receptor signaling, with the latter me- tially be due to its role in inhibiting eu- both the sinoatrial and atrioventricular diating the positive inotropic response karyotic initiation factor 2B (eIF2B)- nodes. These actions are mediated by the (25). M3 muscarinic receptors also appear mediated protein synthesis (40). binding of ACh to M2 muscarinic recep- to regulate pathophysiological responses. Furthermore, RGS2 knockout (KO) mice tors in atrial myocytes (14,15). M2 recep- It has been reported that cholinergic sig- display hypertension under basal condi- tors are coupled to Gi proteins, which naling via M3 receptors in the heart can tions (41) and increased ventricular dys- mediate the decrease in inotropic and lead to cardioprotection after myocardial function and dilation after transverse chronotropic responses through various ischemia, a process thought to occur aortic constriction, thus suggesting a role downstream mechanisms. One mecha- through inhibition of miR-376b-5p (26). for RGS2 signaling in the cardiovascular nism involves direct inhibition of adeny- Furthermore, it was recently shown that response to pathological stimuli (42). lyl cyclase, which leads to decreased pro- upregulation of the M3 muscarinic recep- Evidence suggests that, under physio- duction of adenosine 3′,5′-cyclic tor in mice attenuates angiotensin II logical conditions, parasympathetic tone monophosphate (cAMP) and inhibition (Ang II)-induced cardiac hypertrophic re- is the main regulator of heart rate and of protein kinase A (PKA) (16,17). Mus- sponse (27). cardiac activity (43,44). Therefore, it is carinic receptor activation can also lead In addition to its direct effects on the likely that, under pathological conditions, to indirect inhibition of L-type Ca2+ chan- heart via muscarinic receptors, it is well cholinergic tone balances sympathetic nels through a decrease in cAMP produc- known that ACh is also critical in regu- signaling to prevent adverse effects asso- tion (18). Furthermore, the negative in- lating sympathetic signaling, since it ciated with increased activation of otropic and chonotropic effects observed mediates fast transmission through β-adrenergic receptor–mediated signal- after activation of M2 receptors are due sympathetic ganglia by activating ing. This result may serve to prevent car- to hyperpolarization of atrial cells fol- α-neurotoxin–sensitive postsynaptic diomyocyte remodeling associated with lowing the direct activation of inwardly nicotinic ACh receptors (28). In addition, overactivation of the sympathetic system. rectifying ACh-sensitive potassium chan- ACh can mediate slow excitatory synap- Thus, cholinergic activity modulation βγ nels (KACh) by the Gi subunit that is tic transmission at sympathetic ganglia may serve as a new target for the treat- normally activated by the M2 receptor via post-ganglionic M1 receptors (29). ment of cardiac disease. Here, recent (19). In addition, activation of muscarinic Furthermore, ACh can also regulate findings highlighting the importance of receptors leads to negative chronotropic sympathetic signaling by binding to altered autonomic regulation, especially responses due to decreased cAMP levels, presynaptic receptors on sympathetic cholinergic signaling, and its implications which results in downstream inhibition nerve terminals innervating the heart. in cardiac disease will be highlighted. of the HCN (hyperpolarization activa- Activation of M1 muscarinic receptors at tion, cyclic nucleotide–gated) channel- presynaptic sympathetic nerves can in- AUTONOMIC NERVOUS SYSTEM IN mediated “funny” current (If) (20,21). crease norepinephrine (NE) release (30), HEART FAILURE: ENHANCED The M2 receptor is the main mus- whereas M2 muscarinic
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