Figure 7.

Mevalonate cascade-stimulated autophagy inhibition increases apoptosis and endoplasmic reticulum stress response and increases cell death (a) Myocardial atrial fibroblast were pretreated with bafilomycin-A1 (0.01 μM, 4 h) and then co-treated with simvastatin (10 μM) for indicated time point. Inhibition of autophagy flux increased LC3β II accumulation, caspase-3, -7 and -9 cleavage and IREα1 and BIP (GRP78) expression. (b) Bafilomycin-A1 (5 and 10 nM) pre and then cotreatment with simvastatin (10 μM) significantly increased simvastatin-induced loss of viability of myocardial atrial fibroblast (***P<0.001). Cell viability was measured using MTT assay. (c and d) Mouse embryo fibroblasts that express ATG5 and ATG5 knockout cells were treated with simvastatin (10 μM). ATG5 knockout cells exhibited significantly greater loss of cell viability (measured by MTT assay) in response to simvastatin (***P<0.001) (96 h) (d) and also increased caspase-7 cleavage and BIP expression. Equal loading was confirmed using β-actin