The Effects Of Atorvastatin On Inflammation,stability Of Vulnerable Atherosclerotic Plaques And The Underlying Mechanisms

Atherosclerosis is a chronic disease of intima malfunction and arterial inflammation.Recent studies have demonstrated that autophagy could inhibit inflammatory response in atheroscleorsis and exert subsequent atheroprotective effects.Our previous study has also demonstrated that the role of autophagy in the inhibition of inflammation by atorvastatin in vitro.However,little is known whether atorvastatin could up-regulate autophagy level to inhibit inflammatory cytokines secretion,lipid accumulation,and even improve vulnerable plaque stability both in vitro and in vivo.First,using a mouse model of vulnerable atherosclerotic plaque,we explored the effect of atorvastatin(10 or 20 mg/kg/day)on plaque morphology.The results proved that atorvastatin could enhance the stability of vulnerable atherosclerotic plaques and reduce the lesion area in aortas.Furthermore,we found atorvastatin inhibit inflammatory response,such as IL-1β,TNF-α and IL-18 release,and attenuate lipid deposition both in vitro and in vivo.Unfortunately,all these beneficial effects were abolished by 3-MA,an antophagy inhibitor.Atorvastatin treatment up-regulated the expression of autophagy-related protein microtubule-associated protein light chain(LC3B),down-regulated the expression of SQSTM1/p62,which suggested autophagy was activated both in vulnerable plaques and in cells by atorvastatin.Meanwhile,transmission electron microscopy further testified the increased autophagy activity in vulnerable atherosclerotic plaques by atorvastatin.In addition,atorvastatin significantly inhibited the phosphorylation of mTOR,and NLRP3 inflammasome,which strongly suggest the involvement of mTOR pathway.Our study may have introduced a new role of atorvastatin as an autophagy inducer to exert anti-inflammatory,atheroprotective effects and to stabilize vulnerable atherosclerotic plaques.