Ischemia Impairs the Association Between Connexin 43 and M3 Subtype of Acetylcholine Muscarinic Receptor (M3-mAChR) in Ventricular Myocytes

Yue, Peng; Zhang, Yong; Du, Zhenhong; Xiao, Jing; Pan, Zhenwei; Wang, Ning; Yu, Haijing; Ma, Wencai; Qin, Hong; Wang, Wenhui; Lin, Dao‐Hong; Yang, Baofeng

doi:10.1159/000092074

Cited by 36 publications

(35 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, it is also anticipated that the hyperpolarizing effects associated with the I K1 -enhancing effects of M 3 -mAChR observed in this study would improve cardiac conduction by relieving Na + channels from the inactivated state induced by membrane depolarization in CH. Together with the improving effect of M 3 -mAChR on connexin-43 revealed in our previous study [34], it appears that M 3 -mAChR favors both intracellular conduction (by minimizing Na + channel inactivation) and intercellular excitation propagation (by enhancing connexin-43), which might also contribute to mitigating the adverse electrical remodeling.…”

Section: Discussionsupporting

confidence: 64%

“…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%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 64%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, a large body of evidence indicates that muscarinic acetylcholine receptors, especially M 3 -mAChR, play critical roles in regulating the activity of many important functions of cardiovascular systems (26). Previous studies have demonstrated that M 3 -mAChR may possess a potential role in protecting the heart against ischemia through multiple mechanisms, including the interaction with gap junction channel connexin 43 to maintain cell-cell communication (10), activation of antiapoptotic signal molecule Bcl-2 and p38 mitogen-activated protein kinase and a decrease in Ca 2+ overload induced by myocardial ischemia in ventricular cardiomyocytes (12), which has been known to improve cardiac contraction and hemodynamics by activating intracellular phosphoinositide hydrolysis via a Gq pathway (27).…”

Section: Discussionmentioning

confidence: 99%

“…chemic dysrhythmias) (9). M 3 -mAChR interacts with gap-junctional channel connexin 43 to maintain cell-cell communication and excitation propagation (10). M 3 -mAChR regulates intracellular phosphoinositide hydrolysis to improve cardiac contraction and hemodynamic function (11).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of M3 Muscarinic Receptor Is a Novel Strategy for Preventing Sudden Cardiac Death in Transgenic Mice

Liu¹,

Sun²,

Pan³

et al. 2011

Mol Med

Self Cite

View full text Add to dashboard Cite

The present study was designed to investigate the cardiac benefits of M 3 muscarinic receptor (M 3 -mAChR) overexpression and whether these effects are related to the regulation of the inward rectifying K + channel by microRNA-1 (miR-1) in a conditional overexpression mouse model. A cardiac-specific M 3 -mAChR transgenic mouse model was successfully established for the first time in this study using microinjection, and the overexpression was confirmed by both reverse transcriptase-polymerase chain reaction and Western blot techniques. We demonstrated that M 3 -mAChR overexpression dramatically reduced the incidence of arrhythmias and decreased the mortality in a mouse model of myocardial ischemia-reperfusion (I/R). By using whole-cell patch techniques, M 3 -mAChR overexpression significantly shortened the action potential duration and restored the membrane repolarization by increasing the inward rectifying K + current. By using Western blot techniques, M 3 -mAChR overexpression also rescued the expression of the inward rectifying K + channel subunit Kir2.1 after myocardial I/R injury. This result was accompanied by suppression of upregulation miR-1. We conclude that M 3 -mAChR overexpression reduced the incidence of arrhythmias and mortality after myocardial I/R by protecting the myocardium from ischemia in mice. This effect may be mediated by increasing the inward rectifying K + current by downregulation of arrhythmogenic miR-1 expression, which might partially be a novel strategy for antiarrhythmias, leading to sudden cardiac death.

show abstract

“…Studies using confocal microscopy and immunostaining showed that M 1 and M 2 muscarinic cholinoreceptors are evenly distributed throughout the surface membrane of ventricular myocytes, whereas muscarinic receptors, which belong to M 3 subtype are predominantly localized on intercalated disks [41,45]. Furthermore, coexpression of M 3 muscarinic cholinoreceptors and connexin 43, a most abundant gap junction channel, has been found in rat ventricular myocytes [45] assuming that these receptors are involved in cell-to-cell communications.…”

Section: Effects Of Subtype-selective Muscarinic Cholinoreceptor Blocmentioning

confidence: 99%

Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

Osadchii

2007

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

This study was designed to determine if chronotropic responses induced by neurally released acetylcholine are modified by subtype-selective blockade of cardiac muscarinic cholinoreceptors. In anesthetized cats, a single burst of vagal stimulation was generated with an incremental time delay after the P wave of the atrial electrogram (P-Stimulus interval). The slope of the relationships between P-Stimulus and P-P intervals was used to assess changes in responsiveness of cardiac pacemaker to vagal effects throughout the cardiac cycle. An increase in P-Stimulus interval over the initial portion (approximately 120 ms) of the cardiac cycle produced a significant increment in lengthening of the P-P interval. Once the maximal negative chronotropic response was achieved, a further increase in P-Stimulus interval by only approximately 25 ms resulted in profound (by 80-90%) reductions in vagal effects, thus yielding a bimodal vagal phase response curve. Antagonists of M1 (pirenzepine), M2 (methoctramine and gallamine), and M3 (4-DAMP) muscarinic cholinoreceptors produced a reduction in the magnitude of maximal lengthening of cardiac cycle as well as an increase in latency of vagal effects. However, the increment in prolongation of P-P interval induced by a given change in timing of vagal stimulation during cardiac cycle was reduced by M1 and M2 muscarinic receptor blockers, but was unaffected by 4-DAMP. None of the antagonists modified the range of P-Stimulus intervals over which the maximum-to-minimum change of vagal responses occurred. Taken together, these data suggest different contribution of various subtypes of cardiac muscarinic receptors into the negative chronotropic responses induced by brief bursts of vagal stimulation.

show abstract

Ischemia Impairs the Association Between Connexin 43 and M3 Subtype of Acetylcholine Muscarinic Receptor (M3-mAChR) in Ventricular Myocytes

Cited by 36 publications

References 29 publications

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

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

Overexpression of M3 Muscarinic Receptor Is a Novel Strategy for Preventing Sudden Cardiac Death in Transgenic Mice

Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

Contact Info

Product

Resources

About