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Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension.
Arterioscler Thromb Vasc Biol. 2013 Jan; 33(1):34-42.AT

Abstract

OBJECTIVE

Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH), and BMPR-II deficiency contributes to idiopathic and experimental forms of PAH. Sildenafil, a potent type-5 nucleotide-dependent phosphodiesterase inhibitor, is an established treatment for PAH, but whether sildenafil affects bone morphogenetic protein (BMP) signaling in the pulmonary circulation remains unknown.

METHODS AND RESULTS

Studies were undertaken in human pulmonary arterial smooth muscle cells (PASMCs) and in vivo in the monocrotaline rat model of PAH. In PASMCs, sildenafil enhanced BMP4-induced phosphorylation of Smad1/5, Smad nuclear localization, and Inhibitor of DNA binding protein 1 gene and protein expression. This effect was mimicked by 8-bromo-cyclic GMP. Pharmacological inhibition or small interfering RNA knockdown of cyclic GMP-dependent protein kinase I inhibited the effect of sildenafil on BMP signaling. In functional studies, we observed that sildenafil potentiated the antiproliferative effects of BMP4 on PASMC proliferation. Furthermore, sildenafil restored the antiproliferative response to BMP4 in PASMCs harboring mutations in BMPR-II. In the monocrotaline rat model of PAH, which is characterized by BMPR-II deficiency, sildenafil prevented the development of pulmonary hypertension and vascular remodeling, and partly restored Smad1/5 phosphorylation and Inhibitor of DNA binding protein 1 gene expression in vivo in monocrotaline exposed rat lungs.

CONCLUSIONS

Sildenafil enhances canonical BMP signaling via cyclic GMP and cyclic GMP-dependent protein kinase I in vitro and in vivo, and partly restores deficient BMP signaling in BMPR-II mutant PASMCs. Our findings demonstrate a novel mechanism of action of sildenafil in the treatment of PAH and suggest that targeting BMP signaling may be beneficial in this disease.

Authors+Show Affiliations

Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23139294

Citation

Yang, Jun, et al. "Sildenafil Potentiates Bone Morphogenetic Protein Signaling in Pulmonary Arterial Smooth Muscle Cells and in Experimental Pulmonary Hypertension." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 1, 2013, pp. 34-42.
Yang J, Li X, Al-Lamki RS, et al. Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2013;33(1):34-42.
Yang, J., Li, X., Al-Lamki, R. S., Wu, C., Weiss, A., Berk, J., Schermuly, R. T., & Morrell, N. W. (2013). Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(1), 34-42. https://doi.org/10.1161/ATVBAHA.112.300121
Yang J, et al. Sildenafil Potentiates Bone Morphogenetic Protein Signaling in Pulmonary Arterial Smooth Muscle Cells and in Experimental Pulmonary Hypertension. Arterioscler Thromb Vasc Biol. 2013;33(1):34-42. PubMed PMID: 23139294.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. AU - Yang,Jun, AU - Li,Xiaohui, AU - Al-Lamki,Rafia S, AU - Wu,Changxin, AU - Weiss,Astrid, AU - Berk,Joachim, AU - Schermuly,Ralph T, AU - Morrell,Nicholas W, Y1 - 2012/11/08/ PY - 2012/11/10/entrez PY - 2012/11/10/pubmed PY - 2013/2/13/medline SP - 34 EP - 42 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 33 IS - 1 N2 - OBJECTIVE: Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH), and BMPR-II deficiency contributes to idiopathic and experimental forms of PAH. Sildenafil, a potent type-5 nucleotide-dependent phosphodiesterase inhibitor, is an established treatment for PAH, but whether sildenafil affects bone morphogenetic protein (BMP) signaling in the pulmonary circulation remains unknown. METHODS AND RESULTS: Studies were undertaken in human pulmonary arterial smooth muscle cells (PASMCs) and in vivo in the monocrotaline rat model of PAH. In PASMCs, sildenafil enhanced BMP4-induced phosphorylation of Smad1/5, Smad nuclear localization, and Inhibitor of DNA binding protein 1 gene and protein expression. This effect was mimicked by 8-bromo-cyclic GMP. Pharmacological inhibition or small interfering RNA knockdown of cyclic GMP-dependent protein kinase I inhibited the effect of sildenafil on BMP signaling. In functional studies, we observed that sildenafil potentiated the antiproliferative effects of BMP4 on PASMC proliferation. Furthermore, sildenafil restored the antiproliferative response to BMP4 in PASMCs harboring mutations in BMPR-II. In the monocrotaline rat model of PAH, which is characterized by BMPR-II deficiency, sildenafil prevented the development of pulmonary hypertension and vascular remodeling, and partly restored Smad1/5 phosphorylation and Inhibitor of DNA binding protein 1 gene expression in vivo in monocrotaline exposed rat lungs. CONCLUSIONS: Sildenafil enhances canonical BMP signaling via cyclic GMP and cyclic GMP-dependent protein kinase I in vitro and in vivo, and partly restores deficient BMP signaling in BMPR-II mutant PASMCs. Our findings demonstrate a novel mechanism of action of sildenafil in the treatment of PAH and suggest that targeting BMP signaling may be beneficial in this disease. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/23139294/Sildenafil_potentiates_bone_morphogenetic_protein_signaling_in_pulmonary_arterial_smooth_muscle_cells_and_in_experimental_pulmonary_hypertension_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.112.300121?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -