A Molecular Mechanism for Therapeutic Effects of cGMP-elevating Agents in Pulmonary Arterial Hypertension

作者：Schwappacher Raphaela^*; Kilic Ana; Kojonazarov Baktybek; Lang Michaela; Diep Thuan; Zhuang Shunhui; Gawlowski Thomas; Schermuly Ralph T; Pfeifer Alexander; Boss Gerry R; Pilz Renate B

来源：Journal of Biological Chemistry, 2013, 288(23): 16557-16566.

DOI：10.1074/jbc.M113.458729

Pulmonary arterial hypertension (PAH) is a progressive, usually fatal disease with abnormal vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients are hyperproliferative and apoptosis-resistant and demonstrate decreased signaling in response to bone morphogenetic proteins (BMPs). Cyclic GMP-elevating agents are beneficial in PAH, but their mechanism(s) of action are incompletely understood. Here we show that BMP signaling via Smad1/5/8 requires cGMP-dependent protein kinase isotype I (PKGI) to maintain PASMCs in a differentiated, low proliferative state. BMP cooperation with cGMP/PKGI was crucial for transcription of contractile genes and suppression of pro-proliferative and anti-apoptotic genes. Lungs from mice with low or absent PKGI (Prkg1(+/-) and Prkg1(-/-) mice) exhibited impaired BMP signaling, decreased contractile gene expression, and abnormal vascular remodeling. Conversely, cGMP stimulation of PKGI restored defective BMP signaling in rats with hypoxia-induced PAH, consistent with cGMP-elevating agents reversing vascular remodeling in this PAH model. Our results provide a mechanism for the therapeutic effects of cGMP-elevating agents in PAH and suggest that combining them with BMP mimetics may provide a novel, disease-modifying approach to PAH therapy.

• 出版日期2013-6-7