Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Wu, Shu-jie; Li, Yuechun; Shi, Zhewei; Lin, Zhonghao; Rao, Zhiheng; Tai, Sichao; Chu, Maoping; Li, Lei; Lin, Jiafeng

doi:10.1161/jaha.117.006510

Cited by 29 publications

(26 citation statements)

References 50 publications

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Section: Discussionmentioning

confidence: 99%

“…In recent decades, studies have shown that CAP induction by vagus nerve stimulation or an α7nAChR agonist reduces inflammation and improves disease states, and inhibiting CAP promotes inflammatory responses and aggravates diseases [ 30 ]. Additionally, investigators found that the spleen is vitally important to inhibit systemic inflammatory response by α7nicotinic agonists or vagus never stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis

Li‐Sha

et al. 2021

Virulence

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Abnormalities in CD4 + T cell (Th cell) differentiation play an important role in the pathogenesis of viral myocarditis (VMC). Our previous studies demonstrated that activation of the cholinergic anti-inflammatory pathway (CAP) alleviated the inflammatory response. In addition, we observed that right cervical vagotomy aggravates VMC by inhibiting CAP. However, the vagus nerve’s effect on differentiation of CD4 + T cells has not been studied in VMC mice to date. In this study, we investigated the effects of cervical vagotomy and the α7nAChR agonist pnu282987 on CD4 + T cell differentiation in a murine myocarditis model (BALB/c) infected with coxsackievirus B3 (CVB3). Splenic CD4 + T cells from CVB3-induced mice obtained and cultured to investigate the potential mechanism of CD4 + T cell differentiation. Each Th cell subset was analyzed by flow cytometry. Our results showed that right cervical vagotomy increased proportions of Th1 and Th17 cells and decreased proportions of Th2 and Treg cells in the spleen. Vagotomy-induced upregulation of T-bet, Ror-γ, IFN-γ, and IL-17 expression while downregulating the expression of Gata3, Foxp3, and IL-4 in the heart. In addition, we observed upregulated levels of proinflammatory cytokines, aggravated myocardial lesions and cellular infiltration, and worsened cardiac function in VMC mice. Pnu282987 administration reversed these outcomes. Furthermore, vagotomy inhibited JAK2-STAT3 activation and enhanced NF-κB activation in splenic CD4 + T cells. The CD4 + T cell differentiation was related to JAK2-STAT3 and NF-κB signal pathways. In conclusion, vagus nerve modulates the inflammatory response by regulating CD4 + T cell differentiation in response to VMC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis

Li‐Sha

et al. 2021

Virulence

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“…The mouse was positioned on a heating pad to maintain body temperature at 37°C and anesthetized by inhaling isoflurane. The echocardiographic ventricular structure was visualized by a blinded investigator in the left parasternal long-axis view, and the left systolic function (LVEF) was measured as previously described [ 20 ]. Other parameters, including the left ventricular (LV) posterior wall end-diastolic and end-systolic thickness, interventricular septal end-diastolic and end-systolic thickness, LV end-diastolic and end-systolic diameter, LV end-diastolic and end-systolic volume, and LV fractional shortening were also measured.…”

Section: Methodsmentioning

confidence: 99%

Nicotinic Agonist Inhibits Cardiomyocyte Apoptosis in CVB3-Induced Myocarditis via α3β4-nAChR/PI3K/Akt-Dependent Survivin Upregulation

Yan

Shi

et al. 2019

Oxidative Medicine and Cellular Longevity

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Background. Cardiomyocyte apoptosis is critical for the development of coxsackievirus B3- (CVB3-) induced myocarditis, which is a common cardiac disease that may result in heart failure or even sudden death. Previous studies have associated CVB3-induced apoptosis with the downregulation of antiapoptotic proteins. Here, attempts were made to examine whether nicotinic acetylcholine receptors (nAChRs), especially α3β4-nAChRs, were a novel therapeutic antiapoptotic target via the activation of survivin, a strong antiapoptotic protein, in viral myocarditis (VMC). Methods and Results. In the present study, we demonstrated that nAChRs, α3β4-nAChR subunits in particular, were present and upregulated in CVB3-infected neonatal rat cardiomyocytes (NRC) and H9c2 cells by RT-qPCR. The function of α3β4-nAChRs was next examined using its specific blocker α-CTX AuIB in vitro. The results of the TUNEL assay and western blot experiments showed that the block of α3β4-nAChRs abrogated nicotine-mediated protection of NRC from CVB3-induced apoptosis, and this effect displayed a substantial correlation with the protein expressions of pAkt, survivin, and Cleaved Caspase-3. Hence, the involvement of the PI3K/Akt pathway was further verified by LY294002, a selective inhibitor of PI3K. As a result, nicotine-mediated induction of pAkt and survivin was abolished by LY294002; meanwhile, apoptotic NRC were increased accompanied by an increase of Cleaved Caspase-3 expression. Regarding CVB3-infected BALB/c mice, the α-CTX AuIB- and LY294002-treated groups had a lower survival rate, deteriorative ventricular systolic function, and more severe inflammation than the nicotine-treated group and the modulation of pAkt, survivin, and Cleaved Caspase-3 protein expressions was similar to that in CVB3-infected NRC. In addition, we found that a nicotinic agonist reduced CVB3 replication in a dose-dependent manner in vitro, which indicates that nAChR activation may serve as a possible protection mechanism of CVB3-induced myocarditis. Conclusions. Our study demonstrated that α3β4-nAChR subunits are essential in the nicotine-mediated antiapoptotic effect of protecting cardiomyocytes from CVB3-induced apoptosis in vivo and in vitro. This protection correlated with the PI3K/Akt pathway and the inducement of the antiapoptotic protein survivin. A combination of these mechanisms serves as a novel protective response to treat viral myocarditis.

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“…Initial reports of the cholinergic anti-inflammatory pathway in the cardiovascular system for clinical use investigated the protective effects of vagus nerve stimulation (VNS) in rats, dogs, rabbits, and pigs in chronic heart failure (Ando et al 2005;Calvillo et al 2011;Hamann et al 2013;Nuntaphum et al 2018;Uemura et al 2010;Vaseghi et al 2017). VNS demonstrated a wide range of effects on the heart following injury, including anti-arrhythmogenic effects following ischemia in rats and rabbits (Ando et al 2005;Brack et al 2011;Wu et al 2017), reduced inflammation and infarct size (Calvillo et al 2011;Wu et al 2017), prevention of remote vascular disfunction (Zhao et al 2013), improved redox status after MI (Shinlapawittayatorn et al 2014;Tsutsumi et al 2008), and has been demonstrated to be tolerable in humans with some efficacy in advanced heart failure states (Klein and Ferrari 2010;Schwartz et al 2008).…”

Section: Cholinergic Anti-inflammatory Pathwaymentioning

confidence: 99%

Stimulating ideas for heart regeneration: the future of nerve-directed heart therapy

2019

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Ischemic heart disease is the leading cause of death worldwide. The blockade of coronary arteries limits oxygenrich blood to the heart and consequently there is cardiomyocyte (CM) cell death, inflammation, fibrotic scarring, and myocardial remodeling. Unfortunately, current therapeutics fail to effectively replace the lost cardiomyocytes or prevent fibrotic scarring, which results in reduced cardiac function and the development of heart failure (HF) in the adult mammalian heart. In contrast, neonatal mice are capable of regenerating their hearts following injury. However, this regenerative response is restricted to the first week of post-natal development. Recently, we identified that cholinergic nerve signaling is necessary for the neonatal mouse cardiac regenerative response. This demonstrates that cholinergic nerve stimulation holds significant potential as a bioelectronic therapeutic tool for heart disease. However, the mechanisms of nerve directed regeneration in the heart remain undetermined. In this review, we will describe the historical evidence of nerve function during regeneration across species. Specifically, we will focus on the emerging role of cholinergic innervation in modulating cardiomyocyte proliferation and inflammation during heart regeneration. Understanding the role of nerves in mammalian heart regeneration and adult cardiac remodeling can provide us with innovative bioelectronic-based therapeutic approaches for treatment of human heart disease.

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Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Cited by 29 publications

References 50 publications

Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis

Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis

Nicotinic Agonist Inhibits Cardiomyocyte Apoptosis in CVB3-Induced Myocarditis via α3β4-nAChR/PI3K/Akt-Dependent Survivin Upregulation

Stimulating ideas for heart regeneration: the future of nerve-directed heart therapy

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