Papers by Oluwaseun Adepoju
D49. GENOTYPES AND PHENOTYPES IN PH, 2009
C95. PULMONARY ARTERIAL HYPERTENSION: THE IDEAS KEEP COMING, 2009
A26. SMOOTH MUSCLE CELLS IN PULMONARY ARTERIAL HYPERTENSION: REGULATION, DIFFERENTIATION, AND PROLIFERATION, 2010
C105. ENDOTHELIAL CELLS IN THE PATHOGENESIS OF PULMONARY ARTERIAL HYPERTENSION, 2010
Human Molecular Genetics, 2013
Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endotheli... more Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endothelial cell (PAEC) proliferation, apoptosis and permeability. Loss-of-function mutations in the bone morphogenetic protein receptor type-II (BMPR-II) are the most common cause of heritable PAH, usually resulting in haploinsufficiency. We previously showed that BMPR-II expression is regulated via a lysosomal degradative pathway. Here, we show that the antimalarial drug, chloroquine, markedly increased cell surface expression of BMPR-II protein independent of transcription in PAECs. Inhibition of protein synthesis experiments revealed a rapid turnover of cell surface BMPR-II, which was inhibited by chloroquine treatment. Chloroquine enhanced PAEC expression of BMPR-II following siRNA knockdown of the BMPR-II transcript. Using blood outgrowth endothelial cells (BOECs), we confirmed that signalling in response to the endothelial BMPR-II ligand, BMP9, is compromised in BOECs from patients harbouring BMPR-II mutations, and in BMPR-II mutant PAECs. Chloroquine significantly increased gene expression of BMP9-BMPR-II signalling targets Id1, miR21 and miR27a in both mutant BMPR-II PAECs and BOECs. These findings provide support for the restoration of cell surface BMPR-II with agents such as chloroquine as a potential therapeutic approach for heritable PAH.
Circulation, 2001
Background Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor... more Background Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-β (TGF-β) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-β superfamily members. Methods and Results For studies of 3 H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-β 1 (10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated 3 H-thymidine incorporation, and TGF-β 1 and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-β 1 stimulated 3 H-thymidine incorporation (200%; P <0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary h...
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Papers by Oluwaseun Adepoju