Potential roles of Kruppel‐like factors in mediating adverse vascular effects of nanomaterials: A review

Abstract

The development of nanotechnology leads to the exposure of human beings to nanomaterials (NMs), and there is a health concern about the adverse vascular effects of NMs. Current data from epidemiology, controlled human exposure, and animal studies suggested that exposure to NMs could induce cardiopulmonary effects. In support of in vivo findings, in vitro studies showed that direct contact of vascular cells with NMs could induce endothelial cell (EC) activation and promote macrophage foam cell formation, although only limited studies showed that NMs could damage vascular smooth muscle cells and promote their phenotypic switch. It has been proposed that NMs induced adverse vascular effects via different mechanisms, but it is still necessary to understand the upstream events. Kruppel‐like factors (KLFs) are a set of C2H2 zinc finger transcription factors (TFs) that can regulate various aspects of vascular biology, but currently, the roles of KLF2 in mediating the adverse vascular effects of NMs have gained little attention by toxicologists. This review summarized current knowledge about the adverse vascular effects of NMs and proposed the potential roles of KLFs in mediating these effects based on available data from toxicological studies as well as the current understanding about KLFs in vascular biology. Finally, the challenges in investigating the role of KLFs in vascular toxicology were also summarized. Considering the important roles of KLFs in vascular biology, further studies are needed to understand the influence of NMs on KLFs and the downstream events.

Influences of Unmodified and Carboxylated Carbon Nanotubes on Lipid Profiles in THP-1 Macrophages: A Lipidomics Study

“…8,9 In particular, it is necessary to evaluate the interactions between MWCNTs and immune cells, such as macrophages, because NMs including MWCNTs entering human bodies will interact with macrophages and consequently induce immunotoxicity (reviewed in the references 10, 11). Indeed, it has been suggested that exposure to NMs including MWCNTs could induce macrophage foam cell formation to promote cardiovascular disease development (reviewed in the references 12, 13), although the mechanisms remain poorly understood.…”

The Role of KLF2 in the Regulation of Atherosclerosis Development and Potential Use of KLF2-Targeted Therapy

“…In total, emerging evidence indicates that endothelial KLF2 is the major MSTF that regulates vascular homeostasis EC metabolism and represents a promising therapeutic target for atherosclerosis treatment and prevention by pharmacological intervention ( Figure 1 ). Recently, other members of the KLF family have been identified, and their involvement in different diseases described [ 50 , 51 ]. While other members of the KLF family also exhibit anti-inflammatory functions, it would be interesting to assess their mechanosensitive properties and potential interaction with KLF2 in the regulation of EC metabolism and athero-protective functions.…”

Comparison of P25 and nanobelts on Kruppel‐like factor‐mediated nitric oxide pathways in human umbilical vein endothelial cells

“…However, the mechanism associated with NM‐induced dysfunction of NO signaling pathways remains poorly understood. Recently, our group proposed that Kruppel‐like factors (TFs), transcription factors (TFs) with crucial regulatory roles in vascular biology, may be involved in NM‐induced endothelial activation (Cao, 2021). Recent studies already reported that many NMs, including multi‐walled nanotubes, halloysite nanotubes (Li, Liu, et al, 2019; Wu, Jiang, et al, 2020), gold (Au) nanorods (Li, Tang, et al, 2019), SiO 2 NMs (Teng et al, 2021), TiO 2 nanoparticles (NPs), titanate nanotubes and nanofibers (Li et al, 2020, 2021), affected KLF‐regulated NO signaling pathways in endothelial cells.…”

“…Interestingly, we reported before that Ti‐based NMs altered the expression of KLFs in endothelial cells (Li et al, 2020) as well as vascular smooth muscle cells (Wang et al, 2018) even at non‐cytotoxic concentrations, indicating a need to re‐evaluate the influences of NMs composed of biocompatible elements on KLFs. But to the best of our knowledge, the roles of physicochemical properties of NMs are not clear (Cao, 2021). Although we reported before that NMs of different morphologies affected KLFs in endothelial cells differently (Li et al, 2020, 2021; Wu, Jiang, et al, 2020), these NMs indeed differed in many physicochemical parameters and, therefore, it is difficult to investigate the exact roles of NM morphologies.…”

“…To investigate the possible mechanism for endothelial activation, the production of intracellular NO was measured by using the fluorescent probe 4‐amino‐5‐methylamino‐2′,7′‐difluorofluorescein diacetate (DAF‐FM DA), and the expression of KLF2 and KLF4 was measured by using real‐time RT‐PCR. We only measured the expression of KLF2 and KLF4 because these KLFs are well‐documented TFs to regulate NO signaling pathways in vascular system (Cao, 2021; Fan et al, 2017).…”