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

Abstract

Atheroprone 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 atheroprone (disturbed) flow that have been described include nuclear factor κB and protein kinase ζ, which is very different from atheroprotective (steady laminar) flow.1 In this issue of Circulation , an article from Xiao et al2 shows the critical role of sterol regulatory element binding protein 2 (SREBP2) on atheroprone flow–mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. In particular, they showed that atheroprone 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 interleukin 1β (IL-1β) expression and endothelial inflammation (Figure 1). In this editorial, we briefly review the NLRP3 inflammasome and SREBP activation system, which play a key role in modulating atheroprone flow–mediated endothelial cell inflammation. We also discuss the following important considerations for the future: the role of local NLRP3 and IL-1β expression, mechanisms for two different types of flow (atheroprone flow versus atheroprotective flow) on SREBP2 activation, and other NLRP3 activators including thioredoxin-interacting protein (TXNIP). Figure 1. Scheme for sterol regulatory element binding protein 2 (SREBP2)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. IL indicates interleukin; Nox, NADPH oxidase; ROS, reactive oxygen species; and TXNIP, thioredoxin-interacting protein. Article see p 632 The inflammasome is a protein complex that serves as a platform for the maturation of caspase-1 subsequent activation, leading to proteolytic maturation and secretion of IL-1β and IL-18 (Figure 8 in Xiao et al2). Three essential components of inflammasome are a sensor protein, the adapter protein ASC, and the inflammatory protease caspase-1. As a sensor protein, Nod-like receptor (NLR) family (NLRP1, NLRP3, and …