Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling

Nguyen, Vince T.; Wu, Yuhong; Guillory, Ashley N.; McConnell, Bradley K.; Fujise, Kenichi; Huang, Ming He

doi:10.1016/j.peptides.2011.11.010

Cited by 14 publications

(4 citation statements)

References 37 publications

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“…The DOR modifies myocardial β‐adrenoceptor and calcitonin gene‐related peptide (CGRP) signalling and responses (Pepe et al ., ; Nguyen et al ., ), and the anti‐infarct effects of DOR activation can be countered by antagonism of β 2 ‐adrenoceptors or CGRP receptors (Huang et al ., ). Unique cardiac protection arising via sustained opioid receptor agonism (see Pharmacological induction of opioid receptor‐mediated cardioprotection, later) is also sensitive to β 2 ‐adrenoceptor antagonism (Peart and Gross, ).…”

Section: Opioid and Opioid Receptor Expression In The Heartmentioning

confidence: 99%

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

Headrick

Hoe

Toit

et al. 2015

British J Pharmacology

134

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Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or 'developed' countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia-reperfusion (I-R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I-R injury. The δ-and κ-opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for μ opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on opioid receptor signalling and protective responses.

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Section: Opioid and Opioid Receptor Expression In The Heartmentioning

confidence: 99%

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

Headrick

Hoe

Toit

et al. 2015

British J Pharmacology

134

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“…The developing heart initially relies on ICA cells as the major source of catecholamines 45 . Published evidence also shows that ICA cells synthesize cardiac intrinsic catecholamines, occurring independently of cardiac sympathetic nerves, either in neonatal or adult hearts, thereby functioning as a critical and integral regulator in mammalian heart development, cardiac pathophysiology and post-heart transplantation support 14 – 17 , 19 , 21 , 46 , 47 . Stimulation of ICA cells enhances epinephrine release to reduce ischemia/reperfusion injury through the δ-opioid-regulated cardioprotective adrenopeptidergic co-signaling pathway 17 , 19 , 48 .…”

Section: Discussionmentioning

confidence: 99%

Intrinsic cardiac adrenergic cells contribute to LPS-induced myocardial dysfunction

et al. 2022

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Intrinsic cardiac adrenergic (ICA) cells regulate both developing and adult cardiac physiological and pathological processes. However, the role of ICA cells in septic cardiomyopathy is unknown. Here we show that norepinephrine (NE) secretion from ICA cells is increased through activation of Toll-like receptor 4 (TLR4) to aggravate myocardial TNF-α production and dysfunction by lipopolysaccharide (LPS). In ICA cells, LPS activated TLR4-MyD88/TRIF-AP-1 signaling that promoted NE biosynthesis through expression of tyrosine hydroxylase, but did not trigger TNF-α production due to impairment of p65 translocation. In a co-culture consisting of LPS-treated ICA cells and cardiomyocytes, the upregulation and secretion of NE from ICA cells activated cardiomyocyte β1-adrenergic receptor driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to crosstalk with NF-κB and mitogen-activated protein kinase pathways. Importantly, blockade of ICA cell-derived NE prevented LPS-induced myocardial dysfunction. Our findings suggest that ICA cells may be a potential therapeutic target for septic cardiomyopathy.

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“…Published evidence has shown that ICA cells synthesize cardiac intrinsic catecholamines occurring independently of cardiac sympathetic nerves, thereby functioning as a critical and integral regulator in mammalian heart development, cardiac pathophysiology and post-heart transplantation support. 14–17,19,21,40,41 Stimulation of ICA cells enhances epinephrine release to reduce ischemia/reperfusion injury through δ-opioid-regulated cardioprotective adrenopeptidergic co-signaling pathway. 17,19,42 Although ICA cell density shows negligible connection with reduced myocardial efficiency in failing myocardium, 18 irregular stimulation of ICA cells increases catecholamine-synthesizing enzymes and cardiac norepinephrine levels.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic cardiac adrenergic cells contribute to septic cardiomyopathy

Yang

Dai

Xing

et al. 2021

Preprint

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Occurring independently of sympathetic nervous system, the intrinsic cardiac adrenergic (ICA) system has been identified as an important regulator in cardiac physiological and pathological processes. However, its role in septic cardiomyopathy remains unknown. Herein, we report that lipopolysaccharide (LPS) dose- and time-dependently increased norepinephrine (NE) release from ICA cells, which aggravates myocardial TNF-α production and dysfunction. Inhibition of NE synthesis in ICA cells alleviated LPS-elicited cardiac dysfunction as well as TNF-α production in Langendorff perfusing hearts. Mechanistically, ICA cell expressed Toll-like receptor 4 (TLR4), activated by LPS, to increase the expression of tyrosine hydroxylase, a key enzyme responsible for NE biosynthesis, via AP-1 binding to its promoter. Surprisingly, LPS-TLR4 signaling triggered no TNF-α production in ICA cells due to the elevated Nfkbia and Tnfaip6 expression. In LPS-treated co-culture of ICA cells and cardiomyocytes, the raised NE from ICA cells activated cardiomyocyte β1-adrenergic receptor (β1-AR), driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to increase the activities of NF-κB and mitogen-activated protein kinase pathways, which were mimicked by dobutamine. Our findings reveal a cell type-specific TLR4 function triggering NE synthesis, but not TNF-α production in inflammatory pathogenesis, and identify ICA cell-derived NE as a paracrine signal in the cross talk among different cardiac cells to enhance myocardial injury during LPS challenge, suggesting that targeting ICA cell-derived NE may be a potential therapeutic strategy for septic cardiomyopathy.

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Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling

Cited by 14 publications

References 37 publications

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

Intrinsic cardiac adrenergic cells contribute to LPS-induced myocardial dysfunction

Intrinsic cardiac adrenergic cells contribute to septic cardiomyopathy

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