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Functional cardiac orexin receptors : role of orexin-B/orexin 2 receptor in myocardial protection
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Patel, Vanlata H., Karteris, Emmanouil, Chen, Jing, Kyrou, Ioannis, Mattu, Harman, Dimitriadis, Georgios K., Rodrigo, Glenn, Antoniades, Charalambos, Antonopoulos, Alexios, Tan, Bee K., Hillhouse, Edward W., Ng, Andre and Randeva, Harpal S. (2018) Functional cardiac orexin receptors : role of orexin-B/orexin 2 receptor in myocardial protection. Clinical Science, 132 (24). pp. 2547-2564. doi:10.1042/CS20180150 ISSN 0143-5221.
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Official URL: http://dx.doi.org/10.1042/CS20180150
Abstract
Orexins/hypocretins exert cardiovascular effects which are centrally mediated. In this study we tested whether orexins and their receptors may also act in an autocrine/paracrine manner in the heart exerting direct effects. Quantitative RT-PCR, immunohistochemical and Western blot analyses revealed that the rat heart expresses orexins and orexin receptors. 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 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 of myosin light chain and troponin-I 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 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.
Item Type: | Journal Article | |||||||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Orexins , Cardiovascular system -- Diseases , Cardiovascular system -- Diseases -- Treatment | |||||||||
Journal or Publication Title: | Clinical Science | |||||||||
Publisher: | Portland Press | |||||||||
ISSN: | 0143-5221 | |||||||||
Official Date: | 13 December 2018 | |||||||||
Dates: |
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Volume: | 132 | |||||||||
Number: | 24 | |||||||||
Page Range: | pp. 2547-2564 | |||||||||
DOI: | 10.1042/CS20180150 | |||||||||
Status: | Peer Reviewed | |||||||||
Publication Status: | Published | |||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||
Date of first compliant deposit: | 26 November 2018 | |||||||||
Date of first compliant Open Access: | 2 January 2019 | |||||||||
RIOXX Funder/Project Grant: |
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Open Access Version: |
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