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Functional cardiac orexin receptors: role of orexin-B/orexin 2 receptor in myocardial protection.

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posted on 2019-08-28, 09:32 authored by VH Patel, E Karteris, J Chen, I Kyrou, HS Mattu, GK Dimitriadis, G Rodrigo, C Antoniades, A Antonopoulos, BK Tan, EW Hillhouse, A Ng, HS Randeva
Orexins/hypocretins exert cardiovascular effects which are centrally mediated. In the present study, we tested whether orexins and their receptors may also act in an autocrine/paracrine manner in the heart exerting direct effects. Quantitative reverse transcription-PCR (RT-PCR), immunohistochemical and Western blot analyses revealed that the rat heart expresses orexins and orexin receptors (OXR). In isolated rat cardiomyocytes, only orexin-B (OR-B) caused an increase in contractile shortening, independent of diastolic or systolic calcium levels. A specific orexin receptor-2 (OX2R) agonist ([Ala11, d-Leu15]-Orexin B) exerted similar effects as OR-B, whereas a specific orexin receptor-1 (OX1R) antagonist (SB-408124) did not alter the responsiveness of OR-B. Treatment of the same model with OR-B resulted in a dose-dependent increase in myosin light chain and troponin-I (TnI) phosphorylation. Following ischaemia/reperfusion in the isolated Langendorff perfused rat heart model, OR-B, but not OR-A, exerts a cardioprotective effect; mirrored in an in vivo model as well. Unlike OR-A, OR-B was also able to induce extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2) and Akt phosphorylation in rat myocardial tissue and ERK1/2 phosphorylation in human heart samples. These findings were further corroborated in an in vivo rat model. In human subjects with heart failure, there is a significant negative correlation between the expression of OX2R and the severity of the disease clinical symptoms, as assessed by the New York Heart Association (NYHA) functional classification. Collectively, we provide evidence of a distinct orexin system in the heart that exerts a cardioprotective role via an OR-B/OX2R pathway.

Funding

This work was supported by the British Heart Foundation [grant number 03/131/16192]; and the Heart Research U.K. [grant number RG2564/08/09].

History

Citation

Clinical Science, 2018, 132 (24), pp. 2547-2564

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

  • VoR (Version of Record)

Published in

Clinical Science

Publisher

Portland Press for Biochemical Society

eissn

1470-8736

Acceptance date

2018-11-22

Copyright date

2018

Available date

2019-08-28

Publisher version

http://www.clinsci.org/content/132/24/2547

Language

en

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