Inhibition of Overactive Transforming Growth Factor–β Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertension

The heterozygous loss of function mutations in the Type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlies the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH, and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effects of currently used therapies on the TGF-β pathway remain unknown. Prostacyclin analogs comprise the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analog, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells (PASMCs) harboring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. Our study demonstrates that this agent inhibits TGF-β1–induced SMAD-dependent and SMAD...