The amiloride derivative phenamil attenuates pulmonary vascular remodeling by activating NFAT and the bone morphogenetic protein signaling pathway.
Pulmonary artery hypertension (PAH) is characterized by elevated pulmonary artery resistance and increased medial thickness due to deregulation of vascular remodeling. Inactivating mutations of the BMPRII gene, which encodes a receptor for bone morphogenetic proteins (BMPs), are identified in ∼60% of familial PAH (FPAH) and ∼30% of idiopathic PAH (IPAH) patients. It has been hypothesized that constitutive reduction in BMP signal by BMPRII mutations may cause abnormal vascular remodeling by promoting dedifferentiation of vascular smooth muscle cells (vSMCs). Here, we demonstrate that infusion of the amiloride analog phenamil during chronic-hypoxia treatment in rat attenuates development of PAH and vascular remodeling. Phenamil induces Tribbles homolog 3 (Trb3), a positive modulator of the BMP pathway that acts by stabilizing the Smad family signal transducers. Through induction of Trb3, phenamil promotes the differentiated, contractile vSMC phenotype characterized by elevated expression of contractile genes and reduced cell growth and migration. Phenamil activates the Trb3 gene transcription via activation of the calcium-calcineurin-nuclear factor of activated T cell (NFAT) pathway. These results indicate that constitutive elevation of Trb3 by phenamil is a potential therapy for IPAH and FPAH.
Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, Box 8486, Boston, MA 02111, USA.
Mun Chun
MC
Chan
Alexandra S
AS
Weisman
Hara
H
Kang
Peter H
PH
Nguyen
Tyler
T
Hickman
Samantha V
SV
Mecker
Nicholas S
NS
Hill
Giorgio
G
Lagna
Akiko
A
Hata
D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D015222:Sodium Channels / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D062565:Acid Sensing Ion Channels; D019485:Bone Morphogenetic Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; C502443:Trib3 protein, rat; C047088:phenylamil; D000584:Amiloride; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases