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J Biol Chem. 2013 Jun 7;288(23):16557-66. doi: 10.1074/jbc.M113.458729. Epub 2013 Apr 23.

A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension.

Author information

1
Department of Medicine, University of California San Diego, La Jolla, California 92093, USA. rschwappacher@ucsd.edu

Abstract

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.

KEYWORDS:

Bone Morphogenetic Protein (BMP); Cyclic GMP (cGMP); Protein Kinase G (PKG); Pulmonary Hypertension; Smad Transcription Factor

PMID:
23612967
PMCID:
PMC3675591
DOI:
10.1074/jbc.M113.458729
[Indexed for MEDLINE]
Free PMC Article
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