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Abstract
In a mouse model of oxygen induced retinopathy (OIR), beta adrenergic receptor (BAR) blockade has been shown to recover hypoxia-associated retinal damages. Although the adrenergic signaling is an important regulator of apoptotic and autophagic processes, the role of BARs in retinal cell death remains to be elucidated. The present study was aimed at investigating whether ameliorative effects of BAR blockers may occur through their coordinated action on apoptosis and autophagy. To this aim, retinas from control and OIR mice untreated or treated with propranolol, a non-selective BAR1/2 blocker, were characterized in terms of expression and localization of apoptosis and autophagy markers. The effects of propranolol on autophagy signaling were also evaluated and specific autophagy modulators were used to get functional information on the autophagic effects of BAR antagonism. Finally, propranolol effects on neurodegenerative processes were associated to an electrophysiological investigation of retinal function by recording electroretinogram (ERG). We found that retinas of OIR mice are characterized by increased apoptosis and decreased autophagy, while propranolol reduces apoptosis and stimulates autophagy. In particular, propranolol triggers autophagosome formation in bipolar, amacrine and ganglion cells that are committed to die by apoptosis in response to hypoxia. Also our data argue that propranolol, through the inhibition of the Akt-mammalian target of rapamycin pathway, activates autophagy which decreases retinal cell death. At the functional level, propranolol recovers dysfunctional ERG by recovering the amplitude of a- and b-waves, and oscillatory potentials, thus indicating an efficient restoring of retinal transduction. Overall, our results demonstrate that BAR1/2 are key regulators of retinal apoptosis/autophagy, and that BAR1/2 blockade leads to autophagy-mediated neuroprotection. Reinstating the balance between apoptotic and autophagic machines may therefore be viewed as a future goal in the treatment of retinopathies.
Highlights
In several retinal disorders, apoptotic pathways are primarily involved in retinal cell death leading to progressive visual dysfunction (Chinskey et al, 2014)
In the oxygen induced retinopathy (OIR) model that very closely recapitulates the pathologic events occurring in retinopathy of prematurity (ROP) (Stahl et al, 2010), mice are exposed to hyperoxia from postnatal day (PD)7 to PD12 when, returning to normoxia, they undergo to relative hypoxia that is felt as ischemia (Smith et al, 1994)
Whether modulation of retinal responses to hypoxia involves a coordinated action of beta adrenergic receptor (BAR) on apoptosis and autophagy remains to be established. We addressed this issue by investigating whether BAR blockade with propranolol ameliorates OIR-associated retinal damage by preventing retinal cell degeneration through a coordinated action on apoptosis and autophagy
Summary
Apoptotic pathways are primarily involved in retinal cell death leading to progressive visual dysfunction (Chinskey et al, 2014). Autophagy is a catabolic pathway that promotes the degradation and recycling of cellular components It functions in retinal cell death, and serves as a cell survival mechanism and its modulation may be either beneficial or deleterious depending on the retinal cell type involved and the disease context (Mitter et al, 2012; Russo et al, 2013; Chinskey et al, 2014; Frost et al, 2014; Boya et al, 2016; Chai et al, 2016; Rosa et al, 2016; Amato et al, 2017). These studies have contributed to lay the ground for several independent clinical trials that have demonstrated the effectiveness of propranolol in counteracting the disease progression in preterm newborns suffering from ROP (Filippi et al, 2013, 2017; Makhoul et al, 2013; Bancalari et al, 2016)
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