Neuregulin-1 Attenuates Doxorubicin-induced Autophagy in Neonatal Rat Cardiomyocytes

Abstract

Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in animal models of doxorubicin (DOX)-induced cardiomyopathy, but the underlying mechanism remains largely unknown. Here, we confirm a role for rhNRG-1 in attenuating DOX-induced autophagy and define the signaling pathways through which it mediates some of its effects. Neonatal rat ventricular myocytes were subjected to different treatments both to induce autophagy and to determine the effects of rhNRG-1 on the process. The rhNRG-1 inhibited DOX-induced autophagy, reduced reactive oxygen species production and increased protein expression of Bcl-2, effects that were recapitulated when the cells were treated with the antioxidant N-acetylcysteine. These effects were blocked by the phosphatidylinositol 3-kinase inhibitor LY294002, pointing to the involvement of the Akt pathway in mediating the process. Inhibition of Bcl-2 expression with small interfering RNA silencing also inhibited rhNRG-1's ability to attenuate DOX-induced autophagy. The rhNRG-1 is a potent inhibitor of DOX-induced autophagy and multiple signaling pathways, including Akt and activation of reactive oxygen species, play important roles in the anti-autophagy effect. The rhNRG-1 is a novel drug that may be effectively therapeutically in protecting further damage in DOX-induced damaged myocardium.

Glial Growth Factor 2 protects doxorubicin exposed cardiomyocytes through BAD/Bcl-2 pathway activation

“…Furthermore, GGF2 exposure produced a twofold increase in Bcl-2 gene expression, a response that contributes to pro-survival signaling. Bcl-2 protein expression was also observed to be upregulated in neonatal rat ventricular myocytes after rHNrg1 treatment [30] and our findings corroborate that observation. The BH3 domain-only apoptosis sensitizer protein BAD, sequesters antiapoptotic molecules like Bcl-2 and prevents them from exerting their anti-apoptotic effects [31].…”

“…Inhibition of Bcl-2 expression using siRNA was found to have effects similar to inhibition of erbB2 which increases susceptibility to doxorubicin toxicity [30]. Our studies extend these findings to show that the type II NRG-1 isoform GGF2 also mediates activation of the erbB pathway and produces a cardioprotective effect dependent on pAKT formation.…”

Development and validation of a nomogram with an autophagy-related gene signature for predicting survival in patients with glioblastoma

“…NRG1, one of the most active members of the epidermal growth factor (EGF)-like family, encodes a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems [24]. An et al [25] reported that NRG1 can inhibit doxorubicin-induced autophagy via multiple signaling pathways to prevent further damage from cardiomyopathy. Previous studies have demonstrated that NRG1 plays an important role in aspects of glioma development and progression, including cell survival, migration, proliferation, and metastasis [26,27].…”

Doxorubicin-induced death in tumour cells and cardiomyocytes: is autophagy the key to improving future clinical outcomes?

“…It has been shown that caspases can cleave Becn1, destroying its pro-autophagic function. [68] Once Becn1 is cleaved, the C-terminal fragment is formed with a newly acquired function to amplify mitochondrial-mediated apoptosis. The BH3 domain of Becn1 showed no pro-apoptotic activity and remained within the N-terminal fragment.…”

“…It has been shown that caspases can cleave Becn1, destroying its pro‐autophagic function . Once Becn1 is cleaved, the C‐terminal fragment is formed with a newly acquired function to amplify mitochondrial‐mediated apoptosis.…”