Abstract 12151: PCSK9 Mediates Atherogenesis

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) negatively regulates the low-density lipoprotein (LDL) receptor (LDLR), resulting in increased LDL cholesterol levels. We have suggested that PCSK9 regulates apolipoprotein B (apoB) metabolism via an autophagic process that is independent of the LDLR. Furthermore, whether PCSK9 plays a causal role in atherogenesis independent of LDLR has been controversial. Here, we investigated the molecular mechanisms by which PCSK9 modulates autophagy and the LDLR-independent effects of PCSK9 on atherogenesis. Methods and Results: Deletion of the PCSK9 gene from atherosclerosis prone LDb ( Ldlr-/-Apobec1-/-) mice resulted in substantially less atherosclerosis (> 4-fold), as well as a substantial reduction of plasma apoB, lipids, and triglyceride-rich lipoproteins, but increased HDL particles. The triple knockout mice had a decreased rate of apoB secretion resulting from increased autophagic flux. The deletion of PCSK9 also had profound influences on aortic endothelial cell response to exposure to LDL. LDL associated with PCSK9 increased the expression of TLR2, Lox-1, ICAM-1, CCL2, CCL7, IL-6, IL-1β, Beclin-1, p62, and TRAF6, compared to LDL without PCSK9. Conclusion: Deletion of PCSK9 markedly decreases apoB production by increasing autophagic flux. The absence of PCSK9 results in decreased lipid levels and marked reduction of atherosclerosis, independent of LDLR. The influence on atherogenesis is in part due to the direct effects of PCSK9 on endothelial cell receptors and on proinflammatory and autophagy molecules. These findings suggest that there may be clinical benefits of PCSK9 inhibition due to mechanisms unrelated to increased LDLR activity.