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 journalArticlepeer-review

33 Scopus citations


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
Issue number3
StatePublished - 2009


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

ASJC Scopus subject areas

  • General Medicine


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