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

Clinical Science - Tập 132 Số 24 - Trang 2547-2564 - 2018
Vanlata H. Patel1, Emmanouíl Karteris2, Jing Chen1, Ioannis Kyrou3,1,4, Harman S. Mattu1,4, Georgios K. Dimitriadis1,4, Glenn C. Rodrigo5, Charalambos Antoniades6, Alexios S. Antonopoulos6, Bee K. Tan1, Edward W. Hillhouse7,8, G. André Ng5, Harpal Randeva3,1,4
1Translational and Experimental Medicine, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K.
2Biosciences, Brunel University, Uxbridge UB8 3PH, U.K.
3Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, U.K.
4Warwickshire 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.
5Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester LE3 9QP, U.K.
6Cardiovascular Medicine Division Radcliffe Department of Medicine, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford OX3 9DU, U.K.
7Department of Medicine, Doha, Weill Cornell University, NY, U.S.A.
8Department of Medicine, University of Leeds, Leeds, U.K.

Tóm tắt

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.

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Clinical Science

Tập 132 Số 24

2547-2564

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