Atheroprone Flow Activation of the Sterol Regulatory Element Binding Protein 2 and Nod-Like Receptor Protein 3 Inflammasome Mediates Focal Atherosclerosis

Athero-prone flow promotes inflammation in endothelial cells, and this process is critical for pathogenesis of many chronic inflammatory conditions such as coronary and carotid artery atherosclerosis, as well as abdominal aortic aneurysm. Signal mediators activated by athero-prone (disturbed) flow that have been described include NF-κB and protein kinase C, which is very different from athero-protective (steady laminar) flow(1). In this issue a publication from Shyy’s lab shows the critical role of sterol regulatory element binding protein 2 (SREBP2) on athero-prone flow-mediated NLRP3 inflammasome activation(2). In particular, they showed that athero-prone flow induced both mature form of SREBP2 (SREBP2-N) and SREBP2 mRNA induction, which transcriptionally increase NADPH oxidase 2 (Nox2) and NLRP3 expression, thereby leading to IL-1β expression and endothelial inflammation (Figure 1). In this editorial, we will briefly review the NLRP3 inflammasome and SREBP activation system, which play a key role in modulating athero-prone flow-mediated EC inflammation. We will also discuss the following important questions for the future; the role of local NLRP3 and IL-1β expression, mechanisms for two different types of flow (athero-prone flow vs. athero-protective flow) on SREBP2 activation, and other NLRP3 activators including thioredoxin-interacting protein (TXNIP).