Inhibition of Src activation reverses pulmonary vascular remodeling in experimental pulmonary arterial hypertension via Akt/mTOR/HIF-1<alpha> signaling pathway

Experimental Cell Research
Pengfei LiuShaoliang Chen

Abstract

Pulmonary arterial hypertension (PAH) is a diffuse pulmonary microvascular remodeling disease accompanied by malignant proliferation of pulmonary artery smooth muscle cells (PASMCs), which causes persistent pulmonary artery pressure elevation, right ventricular hypertrophy (RVH) and death. However, current therapies targeting pulmonary vascular remodeling and RVH remain poorly effective in reversing PAH. Overactivation of the protein tyrosine kinase Src plays an important role in tumor cell growth, proliferation and invasion; we thus hypothesized that inhibitors targeting Src activation could reverse experimental PAH. We demonstrated that Src was markedly activated in hypoxia-stimulated PASMCs from donors and PASMCs isolated from PAH patients. We investigated the effects of the Src-selective inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) and berberine (BBR) on PAH-PASMC proliferation and migration by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU) and wound-healing assays. Our in vitro results showed that inhibition of Src (Tyr416) phosphorylation repressed PAH-PASMC proliferation and migration by inhibiting hypoxia-inducible...Continue Reading

Citations

Mar 11, 2020·Frontiers in Bioengineering and Biotechnology·Tomoshi TsuchiyaTakeshi Nagayasu
Dec 22, 2019·International Journal of Molecular Sciences·Robert AncuceanuMihaela Dinu
Sep 4, 2020·The Journal of Clinical Investigation·Soni Savai PullamsettiRajkumar Savai
Dec 4, 2020·Biomedicines·Crystal M GhantousAsad Zeidan
Mar 7, 2021·International Journal of Molecular Sciences·Aleksandra BabichevaJason X-J Yuan
Apr 21, 2021·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Giana Blume CorssacAdriane Belló-Klein

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