PMID- 30467191 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20210109 IS - 1470-8736 (Electronic) IS - 0143-5221 (Print) IS - 0143-5221 (Linking) VI - 132 IP - 24 DP - 2018 Dec 21 TI - Functional cardiac orexin receptors: role of orexin-B/orexin 2 receptor in myocardial protection. PG - 2547-2564 LID - 10.1042/CS20180150 [doi] AB - 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(11), d-Leu(15)]-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. CI - (c) 2018 The Author(s). FAU - Patel, Vanlata H AU - Patel VH AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. FAU - Karteris, Emmanouil AU - Karteris E AUID- ORCID: 0000-0003-3231-7267 AD - Biosciences, Brunel University, Uxbridge UB8 3PH, U.K. Harpal.Randeva@warwick.ac.uk emmanouil.karteris@brunel.ac.uk. FAU - Chen, Jing AU - Chen J AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. FAU - Kyrou, Ioannis AU - Kyrou I AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. AD - Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) and Human Metabolism Research Unit (HMRU) University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, U.K. AD - Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, U.K. FAU - Mattu, Harman S AU - Mattu HS AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. AD - Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) and Human Metabolism Research Unit (HMRU) University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, U.K. FAU - Dimitriadis, Georgios K AU - Dimitriadis GK AUID- ORCID: 0000-0002-6662-804X AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. AD - Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) and Human Metabolism Research Unit (HMRU) University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, U.K. FAU - Rodrigo, Glenn AU - Rodrigo G AD - Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester LE3 9QP, U.K. FAU - Antoniades, Charalambos AU - Antoniades C AD - Cardiovascular Medicine Division Radcliffe Department of Medicine, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford OX3 9DU, U.K. FAU - Antonopoulos, Alexios AU - Antonopoulos A AD - Cardiovascular Medicine Division Radcliffe Department of Medicine, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford OX3 9DU, U.K. FAU - Tan, Bee K AU - Tan BK AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. FAU - Hillhouse, Edward W AU - Hillhouse EW AD - Department of Medicine, Doha, Weill Cornell University, NY, U.S.A. AD - Department of Medicine, University of Leeds, Leeds, U.K. FAU - Ng, Andre AU - Ng A AD - Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester LE3 9QP, U.K. FAU - Randeva, Harpal S AU - Randeva HS AD - Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K. Harpal.Randeva@warwick.ac.uk emmanouil.karteris@brunel.ac.uk. AD - Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) and Human Metabolism Research Unit (HMRU) University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, U.K. AD - Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, U.K. LA - eng GR - FS/16/15/32047/BHF_/British Heart Foundation/United Kingdom GR - RG/17/3/32774/BHF_/British Heart Foundation/United Kingdom GR - 03/131/16192/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181213 PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 0 (Cardiotonic Agents) RN - 0 (HCRTR1 protein, human) RN - 0 (HCRTR2 protein, human) RN - 0 (Hcrtr1 protein, rat) RN - 0 (Hcrtr2 protein, rat) RN - 0 (Myosin Light Chains) RN - 0 (Orexin Receptors) RN - 0 (Orexins) RN - 0 (Troponin I) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM CIN - Clin Sci (Lond). 2019 Apr 4;133(7):853-857. PMID: 30948623 MH - Aged MH - Animals MH - Calcium Signaling MH - Cardiotonic Agents/*pharmacology MH - Disease Models, Animal MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Female MH - Humans MH - Isolated Heart Preparation MH - Male MH - Middle Aged MH - Myocardial Contraction/*drug effects MH - Myocardial Infarction/metabolism/pathology/physiopathology/*prevention & control MH - Myocardial Reperfusion Injury/metabolism/pathology/physiopathology/*prevention & control MH - Myocytes, Cardiac/*drug effects/metabolism/pathology MH - Myosin Light Chains/metabolism MH - Orexin Receptors/*agonists/genetics/metabolism MH - Orexins/*pharmacology MH - Phosphorylation MH - Pregnancy MH - Rats, Wistar MH - Troponin I/metabolism MH - Ventricular Function, Left/*drug effects PMC - PMC6365625 OTO - NOTNLM OT - myocardial infarction OT - orexin receptors OT - orexins COIS- The authors declare that there are no competing interests associated with the manuscript. EDAT- 2018/11/24 06:00 MHDA- 2019/09/17 06:00 PMCR- 2018/12/13 CRDT- 2018/11/24 06:00 PHST- 2018/02/11 00:00 [received] PHST- 2018/11/20 00:00 [revised] PHST- 2018/11/22 00:00 [accepted] PHST- 2018/11/24 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/11/24 06:00 [entrez] PHST- 2018/12/13 00:00 [pmc-release] AID - CS20180150 [pii] AID - 10.1042/CS20180150 [doi] PST - epublish SO - Clin Sci (Lond). 2018 Dec 13;132(24):2547-2564. doi: 10.1042/CS20180150. Print 2018 Dec 21.