Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins

摘要: Abstract HMG-CoA reductase, the proximal rate-limiting enzyme in mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and use linked to improved lung health. We shown that cascade inhibition induces apoptosis autophagy cultured human airway mesenchymal cells. Here, we show simvastatin also endoplasmic reticulum (ER) stress unfolded protein response (UPR) these tested whether coordination of ER stress, determines survival or demise cells exposed statin. observed exposure activates UPR (activated transcription factor 4, activated 6 IRE1α) caspase-4 primary fibroblasts smooth muscle Exogenous apoptosis, UPR, but exogenous was without indicating sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 decreased simvastatin-induced whereas ATG7 ATG3 knockdown significantly increased cell death. In BAX−/−/BAK−/− murine embryonic fibroblasts, simvastatin-triggered apoptotic events were abrogated, flux leading death via necrosis. Our data indicate inhibition, likely associated depletion intermediates, can lead coordinated autophagy, stress. The interplay between pathways appears be principally regulated Bcl-2-family pro-apoptotic proteins. These findings uncover multiple action could contribute refining such agent treatment disease.