Abstract
The mitochondrial uncoupling protein 2 (UCP2) plays a protective function in the vascular disease of both animal models and humans. UCP2 downregulation upon high-salt feeding favors vascular dysfunction in knock-out mice, and accelerates cerebrovascular and renal damage in the stroke-prone spontaneously hypertensive rat. Overexpression of UCP2 counteracts the negative effects of high-salt feeding in both animal models. We tested in vitro the ability of UCP2 to stimulate autophagy and mitophagy as a mechanism mediating its protective effects upon high-salt exposure in endothelial and renal tubular cells. UCP2 silencing reduced autophagy and mitophagy, whereas the opposite was true upon UCP2 overexpression. High-salt exposure increased level of reactive oxygen species (ROS), UCP2, autophagy and autophagic flux in both endothelial and renal tubular cells. In contrast, high-salt was unable to induce autophagy and autophagic flux in UCP2-silenced cells, concomitantly with excessive ROS accumulation. The addition of an autophagy inducer, Tat-Beclin 1, rescued the viability of UCP2-silenced cells even when exposed to high-salt. In summary, UCP2 mediated the interaction between high-salt-induced oxidative stress and autophagy to preserve viability of both endothelial and renal tubular cells. In the presence of excessive ROS accumulation (achieved upon UCP2 silencing and high-salt exposure of silenced cells) autophagy was turned off. In this condition, an exogenous autophagy inducer rescued the cellular damage induced by excess ROS level. Our data confirm the protective role of UCP2 toward high-salt-induced vascular and renal injury, and they underscore the role of autophagy/mitophagy as a mechanism counteracting the high-salt-induced oxidative stress damage.
Highlights
Cardiovascular diseases represent a major health issue for which new preventive and therapeutic strategies are needed, mostly based on a deeper knowledge of the underlying pathogenic mechanisms
We previously demonstrated that uncoupling protein 2 (UCP2) is downregulated by ageing and by highsalt feeding in the animal model of stroke-prone spontaneously hypertensive rat (SHRSP), promoting renal and cerebrovascular damage in this model [3,4,5,6,7]
In the absence of UCP2, autophagy is no longer activated with a significant impairment of the cell viability
Summary
Cardiovascular diseases represent a major health issue for which new preventive and therapeutic strategies are needed, mostly based on a deeper knowledge of the underlying pathogenic mechanisms. The UCP2 overexpression autophagy stimulation on cell viability, when cells are increased the autophagy markers in both cell lines (Fig. 1B, D) This exposed to high-salt, we assessed the rate of cell viability, evidence demonstrates that UCP2 tightly interacts with autop- apoptosis and necrosis in both endothelial and renal tubular cells hagy. Did not respond to bafilomycin treatment, suggesting that autophagy and autophagosome formation were suppressed in UCP2 mediates the link between ROS and autophagy upon these conditions (Fig. 3B, D) These results were corroborated by high-salt condition the observation that an increased number of both autophago- In a separate set of studies performed in the endothelial cell line we somes (yellow and red fluorescent dots) and autolysosomes (red assessed the rate of ROS accumulation depending on the specific dots only) was present in cells exposed to high-salt whereas only experimental condition. Reaches a very high level, such as that observed following UCP2 silencing, the autophagy machinery is no longer activated, not even by alternative endogenous stimuli
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