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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 6, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp233
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Reducing Ischemia/Reperfusion Injury through {delta}-Opioid-Regulated Intrinsic Cardiac Adrenergic Cells: Adrenopeptidergic Co-signaling

Ming-He Huang, MD, PhD1, Vincent Nguyen, MD, PhD1, Yewen Wu, MS1, Saurabh Rastogi, MD1, Charles Y. Lui, MD1, Yochai Birnbaum, MD1, Hui-Qun Wang, MD2, David L. Ware, MD1, Madhu Chauhan, PhD3, Nisha Garg, PhD4, Kian-Keong Poh, MD5, Lei Ye, MD5, Abdul Razakjr Omar, MD5, Huay-Cheem Tan, MD5, Barry F. Uretsky, MD1 and Kenichi Fujise, MD1

1 Department of Internal Medicine, Cardiology Division (M-HH, VN, SR, YW, YB, CYL, DLW, BFU, KF)
2 Research Histopathology Core (H-QW)
3 Department of Obstetrics and Gynecology (MC)
4 Department of Immunology and Microbiology (NG), University of Texas Medical Branch, Galveston, Texas
5 Cardiac Department (K-KP, YL, ARO, H-CT), National University Hospital, Singapore

Address for correspondence: Dr. Ming-He Huang, University of Texas Medical Branch, Department of Internal Medicine, Cardiology Division, 5.106 John Sealy Annex, 301 University Boulevard, Galveston, TX 77555-0553, Tel: (409) 772-2410, Fax: (409) 772-4982, Email: mihuang{at}utmb.edu

Aim: 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 Result: 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 DPDPE increased CGRP release from ICA cells in denervated rat heart. In an ischemia/reperfusion rat model, pre-ischemic 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 (pAkt) levels. This effect was abolished in the presence of β2-AR/CGRP-R blockade. TUNEL 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

Conclusion: ICA cells constitute a {delta}-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through β2-AR/CGRP-R co-signaling, resulting in activation of an anti-apoptotic pathway during ischemia/reperfusion.

KEYWORDS Apoptosis; β2-adrenergic receptor; CGRP; ICA cell; ischemia/reperfusion

Time for primary review: 29 Days


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