Interaction between mTOR pathway inhibition and autophagy induction attenuates adriamycin-induced vascular smooth muscle cell senescence through decreased expressions of p53/p21/p16.

ABSTRACT

Cellular senescence is related to aging and extremely stable proliferative arrest with active metabolism. Senescent cells can activate mammalian target of rapamycin (mTOR) pathway, which plays a crucial role in the regulation of cell metabolism, cellular growth, and autophagy in senescence-associated cardiovascular diseases. Therefore, we examined whether mTOR pathway could induce cellular senescence by inhibition of autophagy in vascular smooth muscle cells (VSMCs). We found that adriamycin-induced VSMC senescence is accompanied by increased activity of mTOR, a major controller of cell growth and a negative regulator of autophagy. VSMC senescence induced by activation of mTOR pathway led to reduced levels of signal-associated autophagy proteins, and inhibition of mTOR pathway resulted in a drastic decrease in the number of senescence-associated ß-galactosidase (SA-ß-gal)-stained cells and increased levels of signal-associated autophagy proteins. Autophagic inhibition potentiated adriamycin-induced mTOR pathway activation as well as increase in the number of SA-ß-gal-stained VSMCs. Results of further experiments showed that mTOR pathway inhibition regulates adriamycin-induced expression of senescence markers (p53/p21/p16), which plays an important role in different aspects of cellular aging. Taken together, these results support the idea that intervention to modulate the interaction between mTOR pathway and autophagy could be a potential strategy for longevity.