Oleylethanolamide Activates Ras-Erk Pathway and Improves Myocardial Function in Doxorubicin-Induced Heart Failure

Abstract

Oleylethanolamide (OEA) is a natural fatty acid ethanolamide produced in the heart, but its biological actions in myocardium have not yet been defined. This study was carried out to determine whether OEA could be used to prevent the development of heart failure or improve evolving heart failure. We studied in vivo and in vitro actions of OEA in cardiac muscle. In an animal model of doxorubicin cardiomyopathy, OEA showed robust effects and attenuated the progression of systolic/diastolic dysfunction and ventricular remodeling. During evolving doxorubicin cardiomyopathy, a therapeutic course of OEA treatment partially restored myocardial function. The preventive and therapeutic effects of OEA were associated with significant improvement of survival. To investigate the mechanism of OEA action in cardiac muscle, we have carried out in vitro experiments in cultured cardiomyocytes. The results showed that OEA, through activation of Ras-Raf-1-Mek-Erk signaling, inhibited doxorubicin-induced apoptosis. Additional experiments showed that OEA activation of the Erk pathway involved activation of Neu/ErbB2 receptor, which suggests OEA actions in cardiac muscle might require activation of Neu/ErbB2. In summary, OEA improved ventricular remodeling and augmented cardiac function in doxorubicin cardiomyopathy, possibly involving activation of Neu/ErbB2 and Ras-Erk signaling. These findings suggest OEA is a novel cardioprotective compound that may be used to develop new strategies for the management of cardiomyopathy.

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…This is consistent with saturated fatty acid inhibition of NRG1b activation of myocyte PI3K/Akt signalling, an effect countered by a monounsaturated fatty acid (oleate) (Miller et al, 2009). Moreover, the endogenous monounsaturated fatty acid oleylethanolamide has been shown to activate ErbB2 and RAS-ERK1/2 signalling and improve cardiac function in doxorubicin-induced heart failure (Su et al, 2006). Thus, shifts in myocardial saturated vs. unsaturated fatty acids, as may occur with metabolic syndrome/hyperlipidaemia, may perturb normal myocardial EGFR signalling, though further work is warranted in terms of impacts on ErbB1/ErbB2 expression and function.…”

“…In cardiac cells, EGFR transactivation has been linked to angiotensin (Rakesh et al, 2010), muscarinic (Krieg et al, 2002;Krieg et al, 2004;Miao et al, 2015), endothelin (Kodama et al, 2002;Chen et al, 2006), opioid (Cao et al, 2005;Cohen et al, 2007;Forster et al, 2007;Zhang et al, 2015), bradykinin (Methner et al, 2009), adrenergic (Noma et al, 2007;Grisanti et al, 2014), adenosine (Williams-Pritchard et al, 2011), and sphoingosine-1 phosphate (S1P) (Hofmann et al, 2009) GPCRs, with transactivation via angiotensin II (Ang II) perhaps the most well studied. Several Gq-linked receptors (Ang II, ET-1, -ARs) may promote cardiac hypertrophy/remodelling, whereas transactivation by adenosine, opioid, bradykinin or muscarinic receptors may be protective, enhancing cell survival.…”

“…Activation of the small GTPase Rac also promotes membrane recruitment of NADPH oxidase complex components (Gregg et al, 2003), while the p47phox subunit (necessary for oxidase activation) is phospho-regulated by both PKC (Fontayne et al, 2002) and the PI3K/Akt pathways (Hoyal et al, 2003). Generation of ROS plays a key role in MMP activation (Wetzker and Bohmer, 2003), increases PTK activity and EGFR phosphorylation via inhibitory oxidation of tyrosine phosphatases targeting Src kinase and EGFR (Salmeen et al, 2003;Chen et al, 2006), and may enhance proteolysis of proteins that repress PTK activity (Liebmann, 2011;George et al, 2013a). These important functions may, in turn, render EGFR transactivation sensitive to age-and disease-dependent perturbations in myocardial ROS and phosphatases.…”

“…However, ROS are also important in MMP activation and EGFR ligand shedding (Wetzker and Bohmer, 2003). In cardiac fibroblasts, for example, ROS are localised upstream of MMP-dependent HB-EGF shedding (in transactivation via endothelin-1), facilitating HB-EGF activation of EGFR via inhibitory oxidation of Src homology 2-containing tyrosine phosphatase (Chen et al, 2006). This is consistent with evidence of ROS-dependent control of protein tyrosine phosphatase 1B activity (Salmeen et al, 2003;van Montfort et al, 2003), known to dephosphorylate EGFR (together with insulin receptor kinase, JAK2 and TYK2 kinases).…”

Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes

“…The protein lysates (1000 mg proteins) were preabsorbed with 20 ml protein A/G agarose beads at 4 8C for 30 min on a rocking platform and spun for 5 min at 10 000 g, the supernatants were incubated with specific primary antibody at 4 8C overnight (Su et al 2006). After incubation with 20 ml protein A/G agarose beads for 1 .…”