Interplay Between KLF4, STAT, IRF and NF-κB in VSMC and Macrophage Plasticity During Vascular Inflammation and Atherosclerosis

Atherosclerosis is characterized by atherosclerotic plaque formation in large and medium vessels, mediated by endothelial cell (EC) dysfunction, altered contractility of Vascular Smooth Muscle Cells (VSMC) and recruitment of blood leukocytes to the injured vascular endothelium. These include macrophages (MØ), T lymphocytes and dendritic cells, which drive the production of many inflammatory mediators and the process of chronic inflammation. Also, de-differentiation or phenotypic switching of VSMCs contributes to vascular remodeling and the pathogenesis of atherosclerosis. Likewise, MØ plasticity and the presence of different phenotypes have a major effect on atherosclerotic plaque formation. The multi-functional transcriptional regulator and pluripotency factor KLF4 acts as a gatekeeper of VSMC phenotypic switching and MØ polarization, during vascular inflammation and atherosclerosis. Similarly, pro-inflammatory pathways activated by TLR4 and IFNγ emerge as key components of VSMC and MØ plasticity, tightly regulated by STATs, IRFs and NF-kB. Recent discoveries predict a collaborative role of these transcription factors in different transcriptional mechanisms connected to inflammation and atherosclerosis. This review provides novel insight into the transcriptional regulatory interplay between KLF4, STATs, IRFs and NF-kB in VSMC phenotypic switching and MØ polarization during atherogenesis. Detailed understanding of these transcriptional networks will enable us to develop novel diagnostic and therapeutic strategies to combat vascular proliferative diseases, including atherosclerosis.