Reducing ischaemia/reperfusion injury through δ-opioid-regulated intrinsic cardiac adrenergic cells

Adrenopeptidergic co-signalling

Ming He Huang, Vincent Nguyen, Yewen Wu, Saurabh Rastogi, Charles Y. Lui, Yochai Birnbaum, Hui Qun Wang, David L. Ware, Madhu Chauhan, Nisha Garg, Kian Keong Poh, Lei Ye, Abdul Razakjr Omar, Huay Cheem Tan, Barry F. Uretsky, Kenichi Fujise

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

AimsThe purpose of this study was to determine whether intrinsic cardiac adrenergic (ICA) cells release calcitonin gene-related peptide (CGRP), exerting synergistic adrenopeptidergic cardioprotection.Methods and resultsIn situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and δ-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The δ-opioid agonist [D-Pen25]-enkephalin (DPDPE) increased CGRP release from ICA cells in denervated rat heart. In an ischaemia/reperfusion rat model, pre-ischaemic treatment with DPDPE reduced infarct size (IS) by 51 ± 16 (P < 0.01). Co-infusion of β2-adrenergic receptor (β2-AR) and CGRP receptor (CGRP-R) antagonists increased IS by 62 ± 23 (P < 0.01) compared with saline and abolished DPDPE-initiated IS reduction. Pre-treatment of ICA cell-myocyte co-culture with the β2-AR/CGRP-R antagonists increased myocyte death rate by 24 ± 4 (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O2). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with β2-AR/CGRP-R agonists reduced hypoxia/re-O2-induced myocyte death by 24 ± 5 (P < 0.01), simulating endogenous neurohormonal effects of ICA cells. Western blot analysis showed that DPDPE markedly increased phosphorylated myocardial Akt levels. This effect was abolished in the presence of β2-AR/CGRP-R blockade. Terminal dUTP nick-end labelling staining analysis of the LV infarct zone demonstrated that DPDPE reduced myocyte apoptosis by 58 ± 19 (P < 0.05), an effect that was eliminated in the presence of β2-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on β-AR/CGRP-R stimulation.ConclusionICA cells constitute a δ-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through β2-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.

Original languageEnglish (US)
Pages (from-to)452-460
Number of pages9
JournalCardiovascular Research
Volume84
Issue number3
DOIs
StatePublished - 2009

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Calcitonin Gene-Related Peptide
D-Penicillamine (2,5)-Enkephalin
Reperfusion Injury
Adrenergic Agents
Opioid Analgesics
Muscle Cells
Adrenergic Receptors
Calcitonin Gene-Related Peptide Receptors
Reperfusion
Ischemia
Opioid Receptors
Coculture Techniques
Radioimmunoassay
Echocardiography
Myocardium
Western Blotting
Apoptosis
Staining and Labeling
Messenger RNA
Mortality

Keywords

  • β2-Adrenergic receptor
  • Apoptosis
  • CGRP
  • ICA cell
  • Ischaemia/reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Reducing ischaemia/reperfusion injury through δ-opioid-regulated intrinsic cardiac adrenergic cells : Adrenopeptidergic co-signalling. / Huang, Ming He; Nguyen, Vincent; Wu, Yewen; Rastogi, Saurabh; Lui, Charles Y.; Birnbaum, Yochai; Wang, Hui Qun; Ware, David L.; Chauhan, Madhu; Garg, Nisha; Poh, Kian Keong; Ye, Lei; Omar, Abdul Razakjr; Tan, Huay Cheem; Uretsky, Barry F.; Fujise, Kenichi.

In: Cardiovascular Research, Vol. 84, No. 3, 2009, p. 452-460.

Research output: Contribution to journalArticle

Huang, MH, Nguyen, V, Wu, Y, Rastogi, S, Lui, CY, Birnbaum, Y, Wang, HQ, Ware, DL, Chauhan, M, Garg, N, Poh, KK, Ye, L, Omar, AR, Tan, HC, Uretsky, BF & Fujise, K 2009, 'Reducing ischaemia/reperfusion injury through δ-opioid-regulated intrinsic cardiac adrenergic cells: Adrenopeptidergic co-signalling', Cardiovascular Research, vol. 84, no. 3, pp. 452-460. https://doi.org/10.1093/cvr/cvp233
Huang, Ming He ; Nguyen, Vincent ; Wu, Yewen ; Rastogi, Saurabh ; Lui, Charles Y. ; Birnbaum, Yochai ; Wang, Hui Qun ; Ware, David L. ; Chauhan, Madhu ; Garg, Nisha ; Poh, Kian Keong ; Ye, Lei ; Omar, Abdul Razakjr ; Tan, Huay Cheem ; Uretsky, Barry F. ; Fujise, Kenichi. / Reducing ischaemia/reperfusion injury through δ-opioid-regulated intrinsic cardiac adrenergic cells : Adrenopeptidergic co-signalling. In: Cardiovascular Research. 2009 ; Vol. 84, No. 3. pp. 452-460.
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abstract = "AimsThe purpose of this study was to determine whether intrinsic cardiac adrenergic (ICA) cells release calcitonin gene-related peptide (CGRP), exerting synergistic adrenopeptidergic cardioprotection.Methods and resultsIn situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and δ-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The δ-opioid agonist [D-Pen25]-enkephalin (DPDPE) increased CGRP release from ICA cells in denervated rat heart. In an ischaemia/reperfusion rat model, pre-ischaemic treatment with DPDPE reduced infarct size (IS) by 51 ± 16 (P < 0.01). Co-infusion of β2-adrenergic receptor (β2-AR) and CGRP receptor (CGRP-R) antagonists increased IS by 62 ± 23 (P < 0.01) compared with saline and abolished DPDPE-initiated IS reduction. Pre-treatment of ICA cell-myocyte co-culture with the β2-AR/CGRP-R antagonists increased myocyte death rate by 24 ± 4 (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O2). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with β2-AR/CGRP-R agonists reduced hypoxia/re-O2-induced myocyte death by 24 ± 5 (P < 0.01), simulating endogenous neurohormonal effects of ICA cells. Western blot analysis showed that DPDPE markedly increased phosphorylated myocardial Akt levels. This effect was abolished in the presence of β2-AR/CGRP-R blockade. Terminal dUTP nick-end labelling staining analysis of the LV infarct zone demonstrated that DPDPE reduced myocyte apoptosis by 58 ± 19 (P < 0.05), an effect that was eliminated in the presence of β2-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on β-AR/CGRP-R stimulation.ConclusionICA cells constitute a δ-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through β2-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.",
keywords = "β2-Adrenergic receptor, Apoptosis, CGRP, ICA cell, Ischaemia/reperfusion",
author = "Huang, {Ming He} and Vincent Nguyen and Yewen Wu and Saurabh Rastogi and Lui, {Charles Y.} and Yochai Birnbaum and Wang, {Hui Qun} and Ware, {David L.} and Madhu Chauhan and Nisha Garg and Poh, {Kian Keong} and Lei Ye and Omar, {Abdul Razakjr} and Tan, {Huay Cheem} and Uretsky, {Barry F.} and Kenichi Fujise",
year = "2009",
doi = "10.1093/cvr/cvp233",
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TY - JOUR

T1 - Reducing ischaemia/reperfusion injury through δ-opioid-regulated intrinsic cardiac adrenergic cells

T2 - Adrenopeptidergic co-signalling

AU - Huang, Ming He

AU - Nguyen, Vincent

AU - Wu, Yewen

AU - Rastogi, Saurabh

AU - Lui, Charles Y.

AU - Birnbaum, Yochai

AU - Wang, Hui Qun

AU - Ware, David L.

AU - Chauhan, Madhu

AU - Garg, Nisha

AU - Poh, Kian Keong

AU - Ye, Lei

AU - Omar, Abdul Razakjr

AU - Tan, Huay Cheem

AU - Uretsky, Barry F.

AU - Fujise, Kenichi

PY - 2009

Y1 - 2009

N2 - AimsThe purpose of this study was to determine whether intrinsic cardiac adrenergic (ICA) cells release calcitonin gene-related peptide (CGRP), exerting synergistic adrenopeptidergic cardioprotection.Methods and resultsIn situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and δ-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The δ-opioid agonist [D-Pen25]-enkephalin (DPDPE) increased CGRP release from ICA cells in denervated rat heart. In an ischaemia/reperfusion rat model, pre-ischaemic treatment with DPDPE reduced infarct size (IS) by 51 ± 16 (P < 0.01). Co-infusion of β2-adrenergic receptor (β2-AR) and CGRP receptor (CGRP-R) antagonists increased IS by 62 ± 23 (P < 0.01) compared with saline and abolished DPDPE-initiated IS reduction. Pre-treatment of ICA cell-myocyte co-culture with the β2-AR/CGRP-R antagonists increased myocyte death rate by 24 ± 4 (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O2). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with β2-AR/CGRP-R agonists reduced hypoxia/re-O2-induced myocyte death by 24 ± 5 (P < 0.01), simulating endogenous neurohormonal effects of ICA cells. Western blot analysis showed that DPDPE markedly increased phosphorylated myocardial Akt levels. This effect was abolished in the presence of β2-AR/CGRP-R blockade. Terminal dUTP nick-end labelling staining analysis of the LV infarct zone demonstrated that DPDPE reduced myocyte apoptosis by 58 ± 19 (P < 0.05), an effect that was eliminated in the presence of β2-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on β-AR/CGRP-R stimulation.ConclusionICA cells constitute a δ-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through β2-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.

AB - AimsThe purpose of this study was to determine whether intrinsic cardiac adrenergic (ICA) cells release calcitonin gene-related peptide (CGRP), exerting synergistic adrenopeptidergic cardioprotection.Methods and resultsIn situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and δ-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The δ-opioid agonist [D-Pen25]-enkephalin (DPDPE) increased CGRP release from ICA cells in denervated rat heart. In an ischaemia/reperfusion rat model, pre-ischaemic treatment with DPDPE reduced infarct size (IS) by 51 ± 16 (P < 0.01). Co-infusion of β2-adrenergic receptor (β2-AR) and CGRP receptor (CGRP-R) antagonists increased IS by 62 ± 23 (P < 0.01) compared with saline and abolished DPDPE-initiated IS reduction. Pre-treatment of ICA cell-myocyte co-culture with the β2-AR/CGRP-R antagonists increased myocyte death rate by 24 ± 4 (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O2). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with β2-AR/CGRP-R agonists reduced hypoxia/re-O2-induced myocyte death by 24 ± 5 (P < 0.01), simulating endogenous neurohormonal effects of ICA cells. Western blot analysis showed that DPDPE markedly increased phosphorylated myocardial Akt levels. This effect was abolished in the presence of β2-AR/CGRP-R blockade. Terminal dUTP nick-end labelling staining analysis of the LV infarct zone demonstrated that DPDPE reduced myocyte apoptosis by 58 ± 19 (P < 0.05), an effect that was eliminated in the presence of β2-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on β-AR/CGRP-R stimulation.ConclusionICA cells constitute a δ-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through β2-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.

KW - β2-Adrenergic receptor

KW - Apoptosis

KW - CGRP

KW - ICA cell

KW - Ischaemia/reperfusion

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DO - 10.1093/cvr/cvp233

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JO - Cardiovascular Research

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