The role of inflammation in vascular disease is well recognized, involving dysregulation of both circulating immune cells as well as the cells of the vessel wall itself. Unrestrained vascular inflammation leads to pathological remodeling that eventually contributes to atherothrombotic disease and its associated sequelae (e.g., myocardial/cerebral infarction, embolism, and critical limb ischemia). Signaling events during vascular inflammation orchestrate widespread transcriptional programs that affect the functions of vascular and circulating inflammatory cells. The Krüppel-like factors (KLFs) are a family of transcription factors central in regulating vascular biology in states of homeostasis and disease. Given their abundance and diversity of function in cells associated with vascular inflammation, understanding the transcriptional networks regulated by KLFs will further our understanding of the pathogenesis underlying several pervasive health concerns (e.g., atherosclerosis, stroke, etc.) and consequently inform the treatment of cardiovascular disease. Within this review, we will discuss the role of KLFs in coordinating protective and deleterious responses during vascular inflammation, while addressing the potential targeting of these critical transcription factors in future therapies.

Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes. Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 has a conserved role in augmenting autophagy and improving vessel function in aged mice. Kruppel-like family of transcription factor 4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging.

TLR3 is one of the major innate immune sensors of dsRNA. The signal transduction pathway activated by TLR3, upon binding to dsRNA, leads to the activation of two major transcription factors: NF-κB and IFN regulatory factor (IRF) 3. In an effort to identify specific chemical modulators of TLR3–IRF3 signal transduction pathway, we developed a cell-based readout system. Using the IFN-stimulated gene 56 promoter-driven firefly luciferase gene stably integrated in a TLR3-expressing HEK293 cell line, we were able to generate a cell line where treatment with dsRNA resulted in a dose-dependent induction of luciferase activity. A screen of two pharmacologically active compound libraries using this system identified a number of TLR3–IRF3 signaling pathway modulators. Among them we focused on a subset of inhibitors and characterized their mode of action. Several antipsychotic drugs, such as sertraline, trifluoperazine, and fluphenazine, were found to be direct inhibitors of the innate immune signaling pathway. These inhibitors also showed the ability to inhibit IFN-stimulated gene 56 induction mediated by TLR4 and TLR7/8 pathways. Interestingly, they did not show significant effects on TLR3-, TLR7-, and TLR8-mediated NF-κB activation. Detailed analysis of the signaling pathway indicated that these drugs might be exerting their inhibitory effects on IRF3 via PI3K signaling pathway. The data presented in this study provide mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs.