Krüppel-Like Factor 2 Suppression by High Glucose as a Possible Mechanism of Diabetic Vasculopathy

Abstract

Background and ObjectivesEndothelial dysfunction is widely observed in diabetes mellitus, resulting in diabetic vascular complications. Krüppel-like factor 2 (KLF2) is implicated as being a key molecule that maintains endothelial function. We evaluated the expression of KLF2 in endothelial cells cultured in high glucose and investigated its functional implication in a diabetic animal model.Subjects and MethodsHuman umbilical vein endothelial cells (HUVECs) were cultured in physiologically high glucose (35 mM) condition. The Otsuka Long Evans Tokushima Fatty (OLETF) strain of rat was used as an excellent model of obese type II diabetes, and their lean littermates are Long Evans Tokushima Otsuka (LETO) rats.ResultsIn HUVECs cultured in physiologically high glucose condition, FOXO1 was activated whereas KLF2 and endothelial nitric oxide synthase (eNOS) expression was near completely abolished, which was completely reversed by FOXO1 small interfering ribonucleic acid. In the vessels harvested from the OLETF rats, the animal model of type II diabetes, KLF2 and eNOS expression were found depleted. When vascular remodeling was induced in the left common carotid artery by reduction of blood flow with partial ligation of the distal branches, greater neointimal hypertrophy was observed in OLETF rats compared with the control LETO rats.ConclusionKLF2 suppression in endothelial cells by high glucose is a possible mechanism of diabetic endothelial dysfunction. The strategy of replenishing KLF2 may be effective for preventing diabetic vascular dysfunction.

A20/TNFAIP3 Increases ENOS Expression in an ERK5/KLF2-Dependent Manner to Support Endothelial Cell Health in the Face of Inflammation

“…KLF2 expression is characteristically high in atherosclerosis-resistant regions of the vasculature but nearly absent at branch points and other atheroprone vascular segments with evidence of inflammation and NF-κB activation (39,54,63). Atheroprone flow, proinflammatory cytokines, and hyperglycemia/diabetes substantially decrease KFL2 expression (39,54,63,64). We confirmed that KLF2 mRNA levels in HCAEC, akin to eNOS, decrease following TNF treatment and that A20 overexpression remarkably prevents this decline.…”

Blood pressure regulation VIII: resistance vessel tone and implications for a pro-atherogenic conduit artery endothelial cell phenotype

“…There is also evidence that eNOS uncoupling (Li et al ., 2011), NADPH oxidase-derived reactive oxygen species (Nam et al ., 2009), fibronectin polymerization (Chiang et al ., 2009), IL-17 signaling (Madhur et al ., 2011), and adhesion molecules such as PECAM-1 (Chen & Tzima, 2009) all contribute to the development of the proatherogenic phenotype induced by partial carotid ligation in mice. Finally, experiments in which the partial ligation model was superimposed onto rodent models of obesity (Lee et al ., 2012) and renovascular hypertension (Jin et al ., 2012) suggest that the pro-atherogenic effects of disturbed flow are more pronounced in the presence of cardiovascular risk factors. This is an area that warrants additional research.…”

Reduced Krüppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy

“…In contrast, chronic exposure to laminar shear stress induces KLF2 expression in glomerular endothelial cells ( 27 ). One study suggests that KLF2 expression is suppressed in cultured endothelial cells exposed to high glucose medium ( 28 ). Based on these findings and the critical role of KLF2 in endothelial cells, we sought to determine whether the expression of KLF2 is regulated in glomeruli of diabetic kidney and whether KLF2 has a cytoprotective role against endothelial cell dysfunction in early DN.…”