The Krüppel-Like Factor 4 as a novel gene therapy target for Hypoxic Pulmonary Hypertension

Persistent low oxygen tension (hypoxia) causes Pulmonary hypertension, resulting in pulmonary vascular inflammation and remodeling and, subsequently, blood flow impairment. Krüppel-like factor 4 (KLF4) is a transcription factor expressed in the pulmonary vasculature endothelium, where it promotes anti-inflammatory and anticoagulant states and increases expression of endothelial nitric oxide synthase, a significant source of vasodilating nitric oxide. Previous studies have also shown that an improved adeno-associated virus (AAV) vector enabled an efficient gene transfer into mice's pulmonary arterial endothelium, thereby allowing therapeutic modulation of gene expression.

In this study, we investigated the therapeutic potential of overexpression of the transcription factor KLF4 to prevent pulmonary hypertension. In vitro experiments were performed using AAV-mediated gene transfer of KLF4 into human umbilical vein endothelial cells (HUVECs) under hypoxic conditions. We analyzed inflammatory markers by real-time qPCR and Western blots. The results showed that overexpression of KLF4 had anti-inflammatory properties and contributed to the maintenance of endothelial barrier function. Besides this, overexpression of KLF4 inhibited the transition of endothelial cells to mesenchymal cells, improved mitochondrial function, and reduced the generation of reactive oxygen species (ROS).

This study's results enable further investigations on AAV-mediated KLF4 overexpression in pulmonary artery endothelial cells in a murine model of chronic hypoxia-induced pulmonary hypertension. 


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