Bosentan for Treatment of Pediatric Idiopathic Pulmonary Arterial Hypertension: State-of-the-Art

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  Figure 1. The mechanisms for bosentan in treating PAH. PDGF-mediated activation of TRKs can upregulation of TRPC6 expression by activating of STAT3 phosphorylation. The resultant increase in the activity of pSTAT3 and ROCs and SOCs would increase Ca2+ to stimulate PASMCs and vasoconstriction. The over-expression of ET-1 can increase levels of PVR by ET-A and ET-B activation through PLC and the downstream in PI3 and DAG pathways. What's more, the balance between vasoconstrictive and vasodilatory mechanisms may be broken by the mutations in BMPR2, and the release of inflammation factors may also induce proliferation of cells. Bosentan, as an endothelin receptor antagonist, directly downregulates TRPC6 and TRK expression by repressing the gene transcription or translation, in addition to blockade of endothelin receptors and their downstream signal transduction pathway traditionally. PASMCs, pulmonary artery smooth muscle cells; DAG, diacylglycerol; PKC, protein kinase C; ROCs, Receptor-operated Ca2+ channels; SOCs, store-operated Ca2+ channels; TKRs, PDGF-mediated activation of tyrosine kinase receptors; pSTAT3, transcription-3 phosphorylation; PDGF, platelet-derived growth factor; TRPC,…