M3 Subtype of Muscarinic Acetylcholine Receptor Promotes Cardioprotection via the Suppression of miR-376b-5p

Pan, Zhenyu; Guo, Yueping; Qi, Hanping; Fan, Kai; Wang, Shu; Zhao, Hua; Fan, Yuhua; Xie, Jing; Guo, Feng; Hou, Yunlong; Wang, Ning; Hu, Rong; Zhang, Yong; Liu, Yan; Du, Zhenhong

doi:10.1371/journal.pone.0032571

Cited by 33 publications

(24 citation statements)

References 42 publications

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“…In cardiomyocytes, M3-mAChR activation during ischemia preserves the phosphorylated levels of sarcolemmal connexin 43 to provide delayed cardioprotection 40 . Further, M3-mAChR-Gαq signaling augments IP3/DAG-mediated calcium release, PKC-mediated phosphorylation, PI3-kinase/Akt-mediated reduced apoptosis, and RGS2 expression 36–38, 41 . CRT has similar effects, including increasing RGS2 expression particularly in clinical responders 7 that may be exerted via M3-mAChR-Gαq signaling.…”

Section: Discussionmentioning

confidence: 97%

“…Whereas the highly prevalent M2-mAChR 18, 19 subtype is selectively coupled to Gαi 17 , the relatively scarce M3-mAChR 23, 24 is highly specific for stimulatory Gαq with putative cardioprotective effects 36–38 . Recent new insights into the molecular structure, function, pharmacology and fundamental physiological role of M3-mAChRs have identified them as a major target for drug development 36, 39 .…”

Section: Discussionmentioning

confidence: 99%

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Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

DeMazumder

Kass

O’Rourke

et al. 2015

Circulation Research

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Rationale Cardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular (LV) function and reduce mortality. The underlying mechanisms are incompletely understood. While β-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored. Objective We hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and β-adrenergic responsiveness in dyssynchronous HF (DHF) that are restored by CRT. Methods and Results Canine tachypaced DHF and CRT models were generated to interrogate responses specific to dyssynchronous vs. resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic and invasive hemodynamic data were collected from normal controls, DHF and CRT models. LV tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (N=42–104 myocytes/model; 6–9 hearts/model). Human LV myocardium was obtained for biochemical analyses from explanted failing (N=18) and non-failing (N=7) hearts. The M2 subtype of muscarinic acetylcholine receptors (M2-mAChR) was upregulated in human and canine HF compared to non-failing controls. CRT attenuated the increased M2-mAChR expression and Gαi-coupling, and enhanced M3-mAChR expression in association with enhanced calcium cycling, sarcomere shortening and β-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both DHF and CRT myocytes. Conclusions Remodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

DeMazumder

Kass

O’Rourke

et al. 2015

Circulation Research

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“…Heart functions are regulated by the autonomic nervous system interacting with the M3 mAChR which is involved in physiological and pathological conditions. Moreover, M3 mAChR promotes cardioprotection via suppression of specific miRNA in myocardial ischaemia [81]. Ischaemic heart disease is a complex disorder of great clinical impact that is often associated with well-known cardiovascular risk factors including hypertension, hyperlipidaemia, diabetes, atherosclerosis, heat failure, and aging [80].…”

Section: Cardiovascular Systemmentioning

confidence: 99%

The Non-Neuronal Cholinergic System in Health and Disease

Beckmann¹,

Lips²

2013

Pharmacology

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Acetylcholine (ACh) is not only a neurotransmitter but is an ancient molecule that can be released by and act on non-neuronal cells. In these cells the system of ACh-synthesizing enzymes, transporters, receptors and degrading enzymes is termed the non-neuronal cholinergic system (NNCS). There is increasing evidence that the NNCS is dysregulated in various diseases and can have an influence on their pathology. However, for many organ systems not much is known about the expression and function of the NNCS. Thus, this review focusses on the role of the NNCS in different organ systems in health and disease. Dysregulation of ACh synthesis and release, mutations or polymorphisms in genes encoding NNCS components, and auto-antibodies against NNCS components are common factors influencing disease progression. Pharmacological agents targeting the NNCS are already successfully in clinical use for some disorders, indicating that interfering with this system is very promising and more research is needed to elucidate the role of the NNCS in different tissues and pathological states.

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“…For example, M 3 -mAChR can interact with cardiac gap-junction channel connexin-43 to maintain normal cell-cell communication [34], activate the anti-apoptotic signal molecule Bcl-2 and p38 mitogen-activated protein kinase (MAPK) [28], enhance endogenous antioxidant capacity, reduce intracellular Ca 2+ overload [27], and promote cardioprotection via inhibiting miR-376b-5p [35], protein kinase C-ε and β-catenin [36] in the setting of myocardial infarction. Atrial M 3 muscarinic receptors mediate positive inotropic effects in mouse [37].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of M3 Muscarinic Receptor Suppressed Adverse Electrical Remodeling in Hypertrophic Myocardium Via Increasing Repolarizing K+ Currents

Chen¹,

Sun²,

Su³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cardiac hypertrophy (CH) is an adaptive response to diverse cardiovascular conditions, which is accompanied by adverse electrical remodeling manifested as abnormal K⁺ channel activities. M₃ subtype of muscarinic acetylcholine receptor (M₃-mAChR) is a novel regulator of cardiac electrical activity. In this study we aim to explore if the overexpression of M₃-mAChR could attenuate the adverse electrical remodeling in CH and then uncover its underlying electrophysiological mechanisms. Methods: Transgenic mice with M₃-mAChR overexpression (M₃-TG) and wild type (WT) mice were subjected to transverse aortic constriction (TAC) to induce CH. Myocardial hypertrophy and cardiac function were quantified by the measurement of echocardiography, electrocardiogram, heart weight and tibia length. Whole-cell and signal-cell patch-clamp were employed to record electrophysiological properties by acute isolation of acutely isolated ventricular cardiomyocytes and Western blot was carried out to evaluate the Kir_2.1and Kv_4.2/4.3 protein levels in left ventricular tissue. Results: Compared with WT group, the elevation of cardiac index, including heart weight/body weight index and heart weight/tibia length index confirmed the myocardial hypertrophic growth induced by TAC. Echocardiography detection revealed that the TAC-treated mice showed an obvious increase in the thickness of left ventricular posterior wall (LVPW) and ejection fraction (EF) due to compensatory hypertrophy, which attenuated by the overexpression of M₃-mAChR. Pressure overload induced a prolongation of QTc interval in WT mice, an effect blunted in M₃-TG mice. Furthermore, compared with WT mice, M₃-mAChR overexpression in hypertrophic myocardium accelerated cardiac repolarization and shortened action potential duration, and thus correcting the prolongation of QTc interval. Moreover, M₃-TG mice have the greater current density of I_K1 and I_to in ventricular myocytes after TAC compared with WT mice. Finally, compared with WT mice, M₃-TG mice expressed higher levels of Kir_2.1 in ventricular myocytes. Conclusion: M₃-mAChR overexpression protected against adverse electrical remodeling in CH by enhancing potassium currents and promoting repolarization.

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M3 Subtype of Muscarinic Acetylcholine Receptor Promotes Cardioprotection via the Suppression of miR-376b-5p

Cited by 33 publications

References 42 publications

Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

The Non-Neuronal Cholinergic System in Health and Disease

Overexpression of M3 Muscarinic Receptor Suppressed Adverse Electrical Remodeling in Hypertrophic Myocardium Via Increasing Repolarizing K+ Currents

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