Pharmacological inhibition of β-catenin prevents EndMT in vitro and vascular remodeling in vivo resulting from endothelial Akt1 suppression.

摘要: Abstract Endothelial to mesenchymal transition (EndMT), where endothelial cells acquire characteristics has been implicated in several cardiopulmonary, vascular and fibrotic diseases. The most commonly studied molecular mechanisms involved EndMT include TGFβ, Notch, interleukin, interferon-γ signaling. As of today, the contributions Akt1, an important mediator TGFβ signaling a key regulator barrier function remains unclear. By using ShRNA based gene silencing approach endothelial-specific inducible Akt1 knockdown (ECKOAkt1) mice, we role vitro pathological remodeling vivo. Stable, silenced (ShAkt1) human microvascular (HMECs) indicated increased expression markers such as N-cadherin α-SMA, phosphorylation Smad2/3, cellular stress via activation p38 MAP Kinase loss nitric oxide synthase (eNOS) accompanied by change morphology HMECs co-localization promoting result was associated with TGFβ2, potent inducer transcription factors Snail1, FoxC2. We observed that hypoxia-induced lung is exacerbated ECKOAkt1 which reversed pharmacological inhibition β-catenin. Thus, provide novel insights into Akt1-mediated β-catenin remodeling, present potential target for therapy various cardiopulmonary diseases involving remodeling.