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

Authors:
Dr  Georgios K Dimitriadis, MD, MSc(Hons), PGDip (Obes), MAcadTM,  SCOPE (Cert.), SCOPE (UK National Fe
Dr Georgios K Dimitriadis, MD, MSc(Hons), PGDip (Obes), MAcadTM, SCOPE (Cert.), SCOPE (UK National Fe
KIng's College Hospital NHS Foundation Trust
Consultant Endocrinologist/Obesity Physician
Subspecialist in Reproductive Endocrinology and Metabolic Medicine
London, London | United Kingdom

Clin Sci (Lond) 2018 12 13;132(24):2547-2564. Epub 2018 Dec 13.

Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K.

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 ([Ala, d-Leu]-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 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 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.

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Source
http://dx.doi.org/10.1042/CS20180150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365625PMC
December 2018
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References

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Increase in sympathetic outflow by paraventricular nucleus stimulation in awake rats
Kannan et al.
Am. J. Physiol. 1989

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