Pulmonary fibrosis is a progressive disease resulting from the abnormal regeneration of cells after apoptosis. The air sacs in the lungs and their supporting structures become inflamed and scarred. As the scarring continues, the lungs stiffen due to the deposition of collagens and other extracellular matrix proteins. The thickening and stiffing of the lung eventually leads to difficulty breathing and lack of oxygen in the bloodstream. Currently, there are no treatments for pulmonary fibrosis, other than lung transplantation. Angiotensin II (Ang II) is a key pro-apoptotic factor in fibrotic tissue diseases. However, the mechanism of Ang II-induced cell death in endothelial cells has not been previously elucidated. Here, I have identified a novel mechanism for Ang II induced apoptosis that involves SHP-2-induced destabilization of Bcl-xL mRNA through reduction of nucleolin binding. The degradation of Bcl-xL mRNA caused an increase in the ratio of pro- to anti-apoptotic proteins, resulting in mitochondrial outer membrane permeabilization and subsequent cellular apoptosis. Hepatocyte growth factor (HGF), a potent endogenous tissue repair factor, has been demonstrated to attenuate lung fibrosis in murine models, but the mechanism is yet unknown. I hypothesized that HGF may prevent endothelial cell apoptosis induced by Ang II. Here, I demonstrated the ability of HGF to inhibit Ang II-induced apoptosis by stabilizing the Bcl-xL mRNA through the phosphorylation and cytoplasmic localization of the nucleolin in both in vitro and in ex vivo lung tissue explants. The known mechanism of HGF inhibition of Ang II-induced apoptosis may provide novel targets for the mitigation of fibrotic diseases in future.
