Krüppel-like factors and vascular wall homeostasis

Abstract

Cardiovascular diseases (CVDs) are major causes of death worldwide. Identification of promising targets for prevention and treatment of CVDs is paramount in the cardiovascular field. Numerous transcription factors regulate cellular function through modulation of specific genes and thereby are involved in the physiological and pathophysiological processes of CVDs. Although Krüppel-like factors (KLFs) have a similar protein structure with a conserved zinc finger domain, they possess distinct tissue and cell distribution patterns as well as biological functions. In the vascular system, KLF activities are regulated at both transcriptional and posttranscriptional levels. Growing in vitro, in vivo, and genetic epidemiology studies suggest that specific KLFs play important roles in vascular wall biology, which further affect vascular diseases. KLFs regulate various functional aspects such as cell growth, differentiation, activation, and development through controlling a whole cluster of functionally related genes and modulating various signaling pathways in response to pathological conditions. Therapeutic targeting of selective KLF family members may be desirable to achieve distinct treatment effects in the context of various vascular diseases. Further elucidation of the association of KLFs with human CVDs, their underlying molecular mechanisms, and precise protein structure studies will be essential to define KLFs as promising targets for therapeutic interventions in CVDs.

Keywords: atherosclerosis; drug development; endothelial cells; inflammation; shear stress; vascular injury; vascular smooth muscle cells.

Figure 1

Schematic representation of KLF functional domains and gene regulation. (A) The transactivation and transrepression domains are located at the N-terminus of KLF proteins. Three consecutive zinc finger motifs are located at the C-terminus. (B) Diagram illustrating the regulatory patterns for KLFs in gene transcription. KLFs induce or repress gene expression in cooperation with co-activators or co-repressors or through interaction with other specific transcription factors. TF, transcription factor; CBP, CREB-binding protein; PCAF, p300/CBP-associated factor; HDACs, histone deacetylases; CtBP, C-terminal-binding protein; Sin3A, SIN3 transcription regulator family member A.

Figure 2

The roles of KLFs in vascular wall biology. KLFs regulate inflammation, proliferation and differentiation in ECs and VSMCs, and are further involved in various vascular diseases, underscoring an important role of KLFs in maintaining vascular homeostasis.

Figure 3

The regulation of KLFs in ECs. In ECs, laminar shear stress (LSS) upregulates, while oscillatory shear stress (OSS) downregulates KLF2 and KLF4. Epigenetic regulation (DNA methylation or histone acetylation) and MEK5–ERK5 signaling mediate the shear stress-dependent regulation of KLF2 and KLF4. KLF2, KLF4, and KLF11 potently inhibit inflammation through suppression of the NF-κB pathway. KLF11 facilitates PPARγ protective effect on ECs, while KLF2 dynamically interacts with co-activators or co-repressors to modulate cell function. Statins upregulate KLF2 in ECs.