Functional Cardiac Orexin Receptors: Role of Orexin-B/Orexin 2 Receptor in Myocardial Protection

Vanlata Patel, Emmanouil Karteris, Jing Chen, Ioannis Kyrou, Harman S Mattu, Georgios K Dimitriadis, Glenn Rodrigo, Charalambos Antoniades, Alexios Antonopoulos, Bee K Tan, Edward W Hillhouse, Andre Ng, Harpal Randeva

Research output: Contribution to journalArticle

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.
Original languageEnglish
JournalClinical Science
Early online date22 Nov 2018
DOIs
Publication statusE-pub ahead of print - 22 Nov 2018

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Orexin Receptors
Phosphorylation
Orexins
Troponin I
Cardiac Myocytes
Reperfusion

Bibliographical note

©2018 The Author(s)
This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence.

Cite this

Patel, Vanlata ; Karteris, Emmanouil ; Chen, Jing ; Kyrou, Ioannis ; Mattu, Harman S ; Dimitriadis, Georgios K ; Rodrigo, Glenn ; Antoniades, Charalambos ; Antonopoulos, Alexios ; Tan, Bee K ; Hillhouse, Edward W ; Ng, Andre ; Randeva, Harpal. / Functional Cardiac Orexin Receptors: Role of Orexin-B/Orexin 2 Receptor in Myocardial Protection. In: Clinical Science. 2018.
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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.",
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Patel, V, Karteris, E, Chen, J, Kyrou, I, Mattu, HS, Dimitriadis, GK, Rodrigo, G, Antoniades, C, Antonopoulos, A, Tan, BK, Hillhouse, EW, Ng, A & Randeva, H 2018, 'Functional Cardiac Orexin Receptors: Role of Orexin-B/Orexin 2 Receptor in Myocardial Protection', Clinical Science. https://doi.org/10.1042/CS20180150

Functional Cardiac Orexin Receptors: Role of Orexin-B/Orexin 2 Receptor in Myocardial Protection. / Patel, Vanlata; Karteris, Emmanouil; Chen, Jing; Kyrou, Ioannis; Mattu, Harman S; Dimitriadis, Georgios K; Rodrigo, Glenn; Antoniades, Charalambos; Antonopoulos, Alexios; Tan, Bee K; Hillhouse, Edward W; Ng, Andre; Randeva, Harpal.

In: Clinical Science, 22.11.2018.

Research output: Contribution to journalArticle

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T1 - Functional Cardiac Orexin Receptors: Role of Orexin-B/Orexin 2 Receptor in Myocardial Protection

AU - Patel, Vanlata

AU - Karteris, Emmanouil

AU - Chen, Jing

AU - Kyrou, Ioannis

AU - Mattu, Harman S

AU - Dimitriadis, Georgios K

AU - Rodrigo, Glenn

AU - Antoniades, Charalambos

AU - Antonopoulos, Alexios

AU - Tan, Bee K

AU - Hillhouse, Edward W

AU - Ng, Andre

AU - Randeva, Harpal

N1 - ©2018 The Author(s) This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence.

PY - 2018/11/22

Y1 - 2018/11/22

N2 - 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.

AB - 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.

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U2 - 10.1042/CS20180150

DO - 10.1042/CS20180150

M3 - Article

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

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