4.4 Article

A Novel Mechanism of Sildenafil Improving the Excessive Proliferation and H2S Production in Pulmonary Arterial Smooth Muscle Cells

Journal

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 74, Issue 4, Pages 355-363

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0000000000000714

Keywords

PASMCs; H2S; proliferation; PAH

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The dysregulation of pulmonary arterial vasoactive mediators or excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) might result in contraction or remodeling of pulmonary blood vessels, leading to related lung diseases. Recent studies suggest that hydrogen sulfide (H2S), a gaseous vasodilator generated in the blood vessels by the enzymes cystathionine g-lyase (CSE) and cystathionine-b-synthase (CBS), could induce the vasodilation, thus improving contraction or remodeling-induced lung diseases. In this study, we hypothesized that PASMCs could produce H2S and relax the pulmonary artery, and its mechanism is related to CSE, CBS, and TRPV4 channels by affecting both the excessive proliferation and pulmonary vasoconstriction in PASMCs. We found that the sildenafil treatment could remarkably promote H2S production and control the proliferation in PASMCs; meanwhile, the protein levels of CSE and CBS and the intracellular concentration of calcium could also be increased by sildenafil. Moreover, the effects of sildenafil could be reversed by a CBS inhibitor or a CSE inhibitor, indicating that sildenafil could affect CSE and CBS to modulate the production of H2S and the proliferation in rat PASMCs. Together, we demonstrated a new mechanism for sildenafil to modulate the synthesis of H2S and cell proliferation in PASMCs by affecting CSE and CBS. TRPV4-dependent Ca2+ events and BMP4 may also be involved.

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