Conclusions
This study reveals a novel protective mechanism by which PCSK9 inhibition enhances autophagy and thereby reduces oxidative stress and inflammation in atherosclerosis.
Methods
Male apolipoprotein E (ApoE)-/- mice were fed a high-fat diet (HFD) for 8 weeks and then received the PCSK9 inhibitor (evolocumab), vehicle, or evolocumab plus chloroquine (CQ) for another 8 weeks. ApoE-/- mice in the control group were fed a regular (i.e., non-high-fat) diet for 16 weeks. Additional in vitro experiments were performed in oxidized low-density lipoprotein (ox-LDL)-treated human acute monocytic leukemia cell line THP-1-derived macrophages to mimic the pathophysiologic process of atherosclerosis.
Results
PCSK9 inhibitor treatment reduced oxidative stress, lipid deposition, and plaque lesion area and induced autophagy in HFD-fed ApoE-/- mice. Most importantly, the administration of chloroquine (CQ), an autophagy inhibitor, significantly reduced the beneficial effects of PCSK9-inhibitor treatment on oxidative stress, lipid accumulation, inflammation, and atherosclerotic lesions in HFD-fed ApoE-/- mice. The in vitro experiments further showed that the PCSK9 inhibitor enhanced autophagic flux in ox-LDL-treated THP-1-derived macrophages, as indicated by increases in the numbers of autophagosomes and autolysosomes. Moreover, the autophagy inhibitor CQ also reduced PCSK9 inhibition-mediated protection against oxidative stress, generation of reactive oxygen species (ROS) and inflammation in ox-LDL-treated THP-1-derived macrophages. Conclusions: This study reveals a novel protective mechanism by which PCSK9 inhibition enhances autophagy and thereby reduces oxidative stress and inflammation in atherosclerosis.