Reducing ischaemia/reperfusion injury through delta-opioid-regulated intrinsic cardiac adrenergic cells: adrenopeptidergic co-signalling.

Abstract

AIMS:

The 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 RESULTS:

In situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and delta-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The delta-opioid agonist [D-Pen(25)]-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 beta(2)-adrenergic receptor (beta(2)-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 beta(2)-AR/CGRP-R antagonists increased myocyte death rate by 24 +/- 4% (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O(2)). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with beta(2)-AR/CGRP-R agonists reduced hypoxia/re-O(2)-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 beta(2)-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 beta(2)-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on beta-AR/CGRP-R stimulation.

CONCLUSION:

ICA cells constitute a delta-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through beta(2)-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.

• Authors: 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
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 84 Issue 3 Pg. 452-60 (Dec 01 2009) ISSN: 1755-3245 [Electronic] England
• PMID: 19581316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-2 Receptor Agonists
• Adrenergic beta-2 Receptor Antagonists
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Receptors, Adrenergic, beta-2
• Receptors, Calcitonin Gene-Related Peptide
• Receptors, Opioid, delta
• Enkephalin, D-Penicillamine (2,5)-
• Proto-Oncogene Proteins c-akt
• Calcitonin Gene-Related Peptide

Topics

• Adrenergic beta-2 Receptor Agonists
• Adrenergic beta-2 Receptor Antagonists
• Animals
• Calcitonin Gene-Related Peptide (metabolism)
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Cell Death (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Enkephalin, D-Penicillamine (2,5)- (pharmacology)
• Heart Ventricles (drug effects, metabolism, pathology)
• Humans
• Myocardial Contraction (physiology)
• Myocardial Reperfusion Injury (prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Receptors, Adrenergic, beta-2 (metabolism)
• Receptors, Calcitonin Gene-Related Peptide (agonists, metabolism)
• Receptors, Opioid, delta (agonists, metabolism)
• Signal Transduction (physiology)