Neuregulin-1 Protects Against Doxorubicin-Induced Apoptosis in Cardiomyocytes Through an Akt-Dependent Pathway

Abstract

In previous studies, it has been shown that recombinant human neuregulin-1(rhNRG-1) is capable of improving the survival rate in animal models of doxorubicin (DOX)-induced cardiomyopathy; however, the underlying mechanism of this phenomenon remains unknown. In this study, the role of rhNRG-1 in attenuating doxorubicin-induce apoptosis is confirmed. Neonatal rat ventricular myocytes (NRVMs) were subjected to various treatments, in order to both induce apoptosis and determine the effects of rhNRG-1 on the process. Activation of apoptosis was determined by observing increases in the protein levels of classic apoptosis markers (including cleaved caspase-3, cytochrome c, Bcl-2, BAX and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining). The activation of Akt was detected by means of western blot analysis. The study results showed that doxorubicin increased the number of TUNEL positive cells, as well as the protein levels of cleaved caspase-3 and cytochrome c, and reduced the ratio of Bcl-2/Bax. However, all of these effects were markedly antagonized by pretreament with rhNRG-1. It was then further demonstrated that the effects of rhNRG-1 could be blocked by the phosphoinositole-3-kinase inhibitor LY294002, indicating the involvement of the Akt process in mediating the process. RhNRG-1 is a potent inhibitor of doxorubicin-induced apoptosis, which acts through the PI3K-Akt pathway. RhNRG-1 is a novel therapeutic drug which may be effective in preventing further damage from occurring in DOX-induced damaged myocardium.

HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner

“…Our demonstration that PI3K and Akt are also required is consistent with previously reported cross-talk between the JAK2/STAT3 and PI3K/Akt pathways in survival signaling in cardiomyocytes (26,42). Our findings also agree with several other studies reporting that Akt activation promotes protection against DOX-induced cardiotoxicity (5,9,21,27), that gene delivery of Akt1 protects against the DOXinduced decline in cardiac function (47), and that Akt1 is the major isoform involved in protection by ischemic preconditioning (23).…”

RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis

“…Like ATF3, NRG1 may be cardioprotective in certain contexts. Indeed, application of NRG1 to cultures of rat cardiomyocytes decreases doxorubicin-induced toxicity [ 25 , 73 , 74 ] and administration of recombinant NRG1 decreases cardiac damage following acute doxorubicin exposure in mice [ 24 , 75 ]. Similarly, KO of the NRG1 receptor erbB4 [ 76 ] or NRG1 haploinsufficiency exacerbates doxorubicin-dependent cardiotoxicity [ 26 ].…”

“…Indeed, doxorubicin drives release of several paracrine factors from the vascular endothelium that can influence the viability and function of cardiomyocytes [ 23 ]. Among these cytokines is the cardioactive growth factor neuregulin-1 (NRG1) [ 23 ], which may protect against acute doxorubicin-induced cardiotoxicity [ 24 , 25 ]. Indeed, NRG1 haploinsufficiency exacerbated doxorubicin-dependent cardiac damage following a single drug bolus [ 26 ], though the role of NRG1 in the chronic phase where sustained growth factor production often turns maladaptive driving ongoing fibrotic remodeling and compromising cardiac contractility remains unclear.…”

Vasorelaxant Mechanism(s) of Clerodendrum Volubile Ethanol Leaf Extract in Normal and Doxorubicin-Treated Endothelium Intact Aortic Rings

“…The endothelium is known to play a crucial role in the development and course of doxorubicin-induced cardiomyopathy which over time culminates into heart failure [3,10]. The reported underlying etiopathological mechanisms of doxorubicin-mediated cardiomyopathy majorly involve increased vascular endothelial permeability [30], and disruptive effect of reactive oxygen species (ROS) on endothelial cellderived endothelin(ET)-1, prostaglandin (PG) I 2 , nitric oxide (NO), and neuregin (NRG)-1 [31][32][33] which promote arteriosclerosis development especially of the aorta [34]. As a result of this, it is imperative to take appropriate measures to protect the endothelium while still ensuring optimal doxorubicin efficacy [10].…”