Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action.

Abstract

The functional involvement of bone morphogenetic protein (BMP) system in primary pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH patient bearing no mutations in BMPR2 gene. A striking increase in the levels of ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6 transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of pphPASMCs, which was opposite to their suppressive effects on the mitosis of the control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas these did not affect control PASMCs. The presence of BMP signaling machinery in pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad-reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2 stimulation. Although Id-1 response was not stimulated by BMP-2 in control PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38 MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the mitotic action is in part MAPK dependent. Thus, the BMP system is strongly involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary arteries in PPH.

• Authors: Masaya Takeda, Fumio Otsuka, Kazufumi Nakamura, Kenichi Inagaki, Jiro Suzuki, Daiji Miura, Hideki Fujio, Hiromi Matsubara, Hiroshi Date, Tohru Ohe, Hirofumi Makino
• Journal: Endocrinology (Endocrinology) Vol. 145 Issue 9 Pg. 4344-54 (Sep 2004) ISSN: 0013-7227 [Print] United States
• PMID: 15192043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Morphogenetic Proteins
• Butadienes
• Enzyme Inhibitors
• Imidazoles
• Ligands
• Nitriles
• Pyridines
• RNA, Messenger
• Receptors, Growth Factor
• U 0126
• Protein Serine-Threonine Kinases
• BMPR1B protein, human
• Bone Morphogenetic Protein Receptors, Type I
• SB 203580

Topics

• Adolescent
• Adult
• Aged
• Bone Morphogenetic Protein Receptors, Type I
• Bone Morphogenetic Proteins (pharmacology)
• Butadienes (pharmacology)
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Hypertension, Pulmonary (physiopathology)
• Imidazoles (pharmacology)
• Ligands
• MAP Kinase Signaling System (drug effects, physiology)
• Mitosis (drug effects, physiology)
• Muscle, Smooth, Vascular (cytology, physiology)
• Nitriles (pharmacology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Pulmonary Artery (cytology, physiology)
• Pyridines (pharmacology)
• RNA, Messenger (analysis)
• Receptors, Growth Factor (genetics, metabolism)