Emerging evidence attributes to orexins/hypocretins (ORs) a protective function in the regulation of cardiovascular responses, heart rate, and hypertension. However, little is known about any direct effect of orexins in the heart function. This is of special relevance considering that cardiovascular diseases, including myocardial infarction and heart failure, are one of the major causes of mortality in the world. In the article published in Clinical Science (2018) (vol. 132, 2547–2564), Patel and colleagues investigated the role of orexins in myocardial protection. Intriguingly, they revealed a source of orexin-A (OR-A) and orexin-B (OR-B) in the heart and cardiomyocytes of the rat. More interestingly, these peptides exert a direct effect on the heart rate by acting in an autocrine/paracrine manner on their respective receptors (OXRs). Indeed, OR-B, but not OR-A, by acting through orexin receptor-2 (OX2R), exerts direct cardioprotective effects in heart failure models. OR-B/OX2R signalling enhances myosin light chain (MLC) and troponin-I (TnI) phosphorylation in a dose-dependent manner, leading to an increase in the strength of their twitch contraction. This effect is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation, both in the rat myocardial tissue and human heart samples. A negative correlation between OX2R expression and clinical severity of symptoms has been found in patients with heart failure. Thus, in addition to the known central effects of orexins/OX2R, the work of Patel and colleagues (Clinical Science (2018) 132, 2547–2564) reports a direct action of OR-B on the heart rate pinpointing to OX2R as a potential therapeutic target for prevention and treatment of cardiovascular disease.
The orexins (ORs), also known as hypocretins, are two small peptides produced by a resctricted number of neurons of the dorsolateral hypothalamus, a brain feeding and autonomic regulatory center [1,2]. The two functional forms of orexin, orexin-A (OR-A) and orexin-B (OR-B), derive from a common precursor, pre-pro-orexin, and act through two G protein-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptors. OR-A has equal affinity for both OX1R and OX2R, while OR-B has a higher affinity for OX2R [2–4]. OXRs are widely distributed through both central and peripheral systems and, according to this distribution, orexins regulate endocrine, metabolic and cardiovascular functions, such as blood pressure and heart rate .
In the central nervous system (CNS), both orexins and OX2R are expressed in the paraventricular nucleus (PVN) , a central area of integration of sympathetic outflow and cardiovascular function [6,7]. Cardiovascular disease, such as myocardial infarction, is one of the main cause of mortality in the world [8,9]. It has been reported that a central action of orexins regulates blood pressure and heart rate [7,6,10] by stimulating sympathetic nerve activity (SNA) , neuroendocrine and autonomic functions [11,12] such as sympathetic vasomotor tone [11–19]. Several studies attribute these cardioprotective effects to OX-A by revealing the ability of excitatory OX-A-positive inputs to the locus ceruleus (LC), rostro-ventral medulla (RVLM), and nucleus tractus solitarius (NTS) [20–22] to increase fire synchronization of norepinephrine (Ne)-containing neurons  and epinephrine (Epi) release . A negative network between OX-A depolarizing inputs to C1-,C2-, and C3-Epi-containing and to A1-, A2-, A4-, A5-, A7-NE-containing neurons  and A1/C1 inhibitory outputs to OX neurons  has been described to regulate centrally evoked sympathetic nervous responses. Accordingly, cardiovascular disease modulates the OR system in the brain, since in two models of spontaneous hypertension, the SHR and BPH/2J Schlager mouse, up-regulation of orexin signaling has been found likely due to an increase in orexin expression and a greater sensitivity of its receptors, possibly Ox2R. Nevertheless, the blockade of orexin receptors attenuates hypertension and stress-related cardiovascular response .
Despite a plethora of anatomical and pharmacological data point toward a critical role for OR-A and OX1R and OX2R in the regulation of cardiovascular function, the direct effect of these neuropeptides on myocardial function has not been studied before.
In their study, Patel and colleagues  identify a direct role of orexin B in the myocardial protection by revealing an autocrine/paracrine action of this peptide in the rat heart. By in vivo, ex vivo and in vitro approaches they demonstrate that the heart not only expresses OXRs but also represent a direct source of orexins. They report a crucial role of OR-B/OX2R pathway, exerted by local ORs, on the control of heart rate. Starting from in vitro study, the authors show that treatment with OR-B leads to a significant increase in Troponin-I (TnI) and myosin light chain (MLC) phosphorylation in ventricular cardiomyocytes accompanied by the increase in their twitch contraction and rescue of contractile functions. Accordingly, acute cardiac events and heart failure are usually characterized by a reduction in the phosphorylation status of TnI .
The second part of Patel and colleagues  study determined the effect of ORs and OXRs agonist on cardiac function. The authors found that treatment with both OR-B and a selective OX2R agonist in pre- or post-myocardial ischemia mouse models is able to reduce the infarct size. In this way, they show a protective role of OXB/OX2R signaling on the cardiac function . The current findings add new aspects of the direct cardioprotective effects of OR-B.
To the best of our knowledge and assessment of the direct role of OR-B/OX2R pathway on myocardial protection, Patel and colleagues  have examined human heart tissue samples from heart failure patients. The authors report a significant negative correlation between the severity of clinical heart failure symptoms and OX2R expression  in accordance with previous data showing poorer cardiac function and great myocardial damage observed in OX2R-deficient mice.
Finally, Patel and colleagues  confirmed data obtained by in vitro rat analysis performing human ex vivo study. In particular, the authors show that OR-B, but not OR-A, induces extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in human myocardial tissue . It is well known that OXRs are able to activate PI3K and ERK cascade and with this work, the authors suggest OR-B-induced cardioprotection mediated by PI3K/Akt pathway, a pathway usually implicated in myocardial protection and recovery following ischemic stress [29,30]. In their work Patel and colleagues propose that OR-B activates the OX2R-ERK1/2-MLC Ca2+ pathway in the heart leading to an increase in cardiomyocytes contractility via direct phosphorylation of the calmodulin-dependent MLC kinase (MLCK) (Figure 1).
OX-B/OX2R-mediated signaling pathway involves ERK1/2-Ca2+/calmodulin-dependent MLCK-mediated phosphorylation of MLC and cTn1 in the heart with a net effect of increased sensitivity and cell length/contractility in cardiomyocytes
The authors conclude that the human and rat heart not only express functional OX2R, but are also a source of orexins. OR-B can exert direct cardioprotective effects leading to a reduction in the infarct size in case of ischemia. Cardiac OXRs can influence contractile tone via mechanisms involving phosphorylation of TnI and MLC and, on the other hand, the severity of heart failure can negatively influence the expression of OX2R.
The work of Patel and colleagues shows for the first time a novel direct effect of OR-B on myocardial function and remodeling. This is of special relevance by considering that orexin antagonism by non-selective dual orexin receptor antagonist (DORA) has been approved by the FDA in 2014 for treating insomnia.
Thus, in addition to the established central effects of orexins/OX2R pathway [31,32], the authors underline the direct effect of OR-B at the heart function shedding light on the novel potential pharmacological utilization of OR-B or of direct OX2R-specific agonists in the prevention and pharmacological intervention for cardiovascular disease prospecting exciting developments in this field over the coming years.
The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the Fondi Ricerca di Ateneo (FRA) 2016-2017 from University of Sannio (to R.I.) and by Intramural Funding of the Endocannabinoid Research Group-Institute of Biomolecular Chemisry of CNR (to L.C.).
R.I. and L.C wrote the text and arranged the figure.