S102 The crosstalk of PDE inhibitor with BMP signalling pathway in human pulmonary arterial smooth muscle cells

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Sildenafil, a potent PDE inhibitor, is an established treatment for PAH. However, the detailed mechanism of its effects on the proliferation of human pulmonary artery smooth muscle cells (hPASMCs) remains unclear.


Because sidenafil is effective treatments for clinical PAH, we hypothesised that these agents enhance Smad1/Id signalling through cGKI in hPASMCs.

Methods and Results

Sildenafil alone has no effect on Smad1 phosphorylation and Id1 gene expression in hPASMCs, However in the presence of BMP4 Sidenafil indeed enhanced BMP-induced phosphorylation of Smad1/5 and Id1 expression in a cGMP/cGKI-dependent manner in hPASMCs. The presumed mechanism is by elevation of intracellular cGKI activity which modulate smad1 phosphorylation and nuclear localisation. Knock down cGKI or use pharmalogical cGMP inhibitor abrogate the effect of Sildenafil on hPASMCs. Furthermore we confirm the rescued pSmad1 signal and elevated proliferation inhibitory effect in hPASMCs from familial pulmonary arterial hypertension patients by Sildenafil.


Sildenafil enhance BMP/Smad through cGMP/cGKI pathway to modulate hPASMCs proliferation.

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