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

Abstract

Kruppel like factor 2 (KLF2) is a mechanosensitive transcription factor participating in the regulation of vascular endothelial cells metabolism. Activating KLF2 in endothelial cells induces eNOS (endothelial nitric oxide synthase) expression, subsequent NO (nitric oxide) release, and vasodilatory effect. In addition, many KLF2-regulated genes participate in the anti-thrombotic, antioxidant, and anti-inflammatory activities, thereby preventing atherosclerosis development and progression. In this review, we summarise recent evidence suggesting that KLF2 plays a major role in regulating atheroprotective effects in endothelial cells. We also discuss several recently identified repurposed drugs and natural plant-based bioactive compounds with KLF2-mediated atheroprotective activities. Herein, we present a comprehensive overview of the role of KLF2 in atherosclerosis and as a pharmacological target for different drugs and natural compounds and highlight the potential application of these phytochemicals for the treatment of atherosclerosis.

The Genetic Architecture of the Etiology of Lower Extremity Peripheral Artery Disease: Current Knowledge and Future Challenges in the Era of Genomic Medicine

“…Histone modifications are shown to be involved in vascular homeostasis (regulated by the KLF2 gene) [ 105 ], the interaction between endothelial cells and vessel wall reactive oxygen species [ 106 ], vascular remodeling in response to laminar stress flow [ 107 ], and vascular endothelial response to hypoxia [ 17 , 108 ].…”

Immune Function of Endothelial Cells: Evolutionary Aspects, Molecular Biology and Role in Atherogenesis

“…Laminar blood flow was found to induce KLF2 and KLF4 expression in the vascular endothelium, whereas KLF2 and KLF4 expression is reduced in areas of impaired blood flow as well as in areas prone to atherosclerosis [ 77 , 78 , 79 , 80 ]. Expression of KLF2 and KLF4 causes increased expression of endothelial nitric oxide synthase (eNOS) and promotes the differentiation of endothelial progenitor cells into endothelial cells [ 74 , 77 , 81 , 82 ]. In addition, KLF2 and KLF4 reduce the expression of inflammatory genes in the endothelium [ 83 ].…”

Molecular Mechanisms Underlying Pathological and Therapeutic Roles of Pericytes in Atherosclerosis

“…The development of atherosclerotic plaques tends to occur at the site of arterial bifurcations and high curvatures, where haemodynamic forces (such as disturbed flow) acting through mechanosensors up-regulate pro-atherogenic and pro-inflammatory genes in ECs (YAP/TAZ pathway in ECs, VCAM1, HIF-1α, NF-κB, KLF2, KLF4 and others) [ 22 ]. KLF2 (Kruppel like Factor 2) is the best-characterised member of the KLF family and mechanosensitive transcription factors with well-studied roles in atherosclerosis [ 23 ]. Furthermore, recent experiments on atherosclerosis resistant BALB mice showed that disturbed blood flow is more prominent in promoting inflammation and atherosclerosis than a high-fat diet [ 24 ].…”