Interplay Between NF‐κB and Kruppel‐like Factors in Vascular Inflammation and Atherosclerosis: Location, Location, Location

A therosclerosis is a highly complex process involving the dynamic interplay between cell types intrinsic (eg, endothelial cells [ECs] and smooth muscle cells [SMCs]) and extrinsic (eg, lymphocytes and myeloid cells) to the blood vessel wall. Over the last several decades extensive work has been conducted that details the many molecular pathways involved in mediating the pathologic vascular inflammation that occurs in atherosclerosis. One of the most important factors in the regulation of this process is the transcription factor nuclear factor jB (NF-jB). NF-jB has been shown to regulate numerous genes involved in the initiation and progression of atherosclerosis, including genes involved in inflammation and immune cell regulation as well as apoptosis and cell proliferation. Genetic approaches have been utilized to identify the different mechanisms and cell type intrinsic actions of NF-jB in mediating atherosclerosis and vascular inflammation. In providing a new example, Yoshida and colleagues in this issue of Journal of the American Heart Association selectively inhibit the NF-jB pathway in SMCs and report attenuation of SMC phenotypic switching and neointima formation after vascular injury. The potential importance and impact of this study requires an understanding of our current knowledge of NF-jB action in other vascular cells. In an effort to assess in vivo the EC-specific function of NF-jB signaling in the pathogenesis of atherosclerosis, Gareus and colleagues generated several different mouse models employing either EC-specific ablation of NEMO/IKKc to interfere with IKK activation or transgenic expression of degradation resistant dominant negative IjBa superrepressor (DNIjBa). EC-restricted inhibition of NF-jB, in Apolipoprotein E knockout (ApoE / ) mice fed a high fat western diet resulted in greatly reduced size and severity of atherosclerotic lesions. Inhibition of NF-jB abrogated expression of adhesion molecules, diminished expression of cytokines and chemokines, and impaired macrophage recruitment to atherosclerotic plaques. These findings support a critical role of the endothelial NF-jB pathway in promoting the pathogenesis of atherosclerosis. Findings from the de Winther laboratory using macrophage-specific inhibition of the NF-jB pathway suggest that the role of NF-jB in this cell type is not as straightforward. Surprisingly, initial studies using LDL receptor deficient (LDLR / ) mice with a macrophage-specific deletion of IjB kinase 2 (IKK2), showed increased atherosclerosis with more advanced lesions and more necrotic plaques. These results highlight the importance of NF-jB in the gene program promoting the resolution of inflammation. In contrast, a subsequent study using bone marrow from p50 deficient mice transplanted into irradiated LDLR / mice demonstrated that hematopoetic deficiency of the p50 subunit of NF-jB results in smaller atherosclerotic lesions with a near complete absence of foam cells. A more recent study in LDLR / mice transplanted with bone marrow from mice with myeloid-specific deletion of IjBa demonstrated larger and more advanced atherosclerotic lesions through enhanced leukocyte recruitment to plaques. These disparate results of NF-jB function in macrophages have yet to be fully reconciled. Despite the in vivo study of the role of the NF-jB pathway in atherosclerosis and vascular inflammation in ECs and macrophages, similar studies investigating this pathway in vascular SMCs have been lacking to date. In this issue of Journal of the American Heart Association, Yoshida and colleagues investigate the cell autonomous role of NF-jB within SMCs by using SM22a Cre to generate mice with SMC-specific expression of a truncated form of IjB (IjBDN) lacking 2 N-terminal phosphorylation sites. SMC-specific expression of IjBDN results in selective sequestration of NF-jB in the cytoplasm of SMCs. Mice with SMC-specific inhibition of the NF-jB pathway displayed a The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Harrington Heart & Vascular Institute, Case Cardiovascular Research Institute, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH. Correspondence to: G. Brandon Atkins, MD, PhD, Case Cardiovascular Research Institute, Iris S. & Bert L. Wolstein Research Building, 2103 Cornell Road, Room 4-542, Cleveland, OH 44106. E-mail: [email protected] J Am Heart Assoc. 2013;2:e000290 doi: 10.1161/JAHA.113.000290. a 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.