Altered MicroRNA Processing in Heritable Pulmonary Arterial Hypertension An Important Role for Smad-8

• Published in: American journal of respiratory and critical care medicine 2011-12, Vol.184 (12), p.1400-1408
• Main Authors: DRAKE, Kylie M, ZYGMUNT, Deborah, MAVRAKIS, Lori, HARBOR, Phyllis, LINGLI WANG, COMHAIR, Suzy A, ERZURUM, Serpil C, ALDRED, Micheala A
• Format: Article
• Language: English
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - metabolism; Cell growth; Cell Proliferation; Cells, Cultured; Endothelium, Vascular - pathology; Familial Primary Pulmonary Hypertension; Female; Gene Expression Profiling; Humans; Hypertension, Pulmonary - genetics; Intensive care medicine; Lungs; Male; Medical sciences; MicroRNAs; MicroRNAs - metabolism; Middle Aged; Muscle, Smooth, Vascular - pathology; Mutation; Mutation - genetics; Pneumology; Proteins; Pulmonary arteries; Pulmonary Artery - pathology; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Signal Transduction - genetics; Smad8 Protein - genetics; Smad8 Protein - metabolism; Smooth muscle; Variance analysis; Veins & arteries
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201106-1130OC

Heritable pulmonary arterial hypertension (HPAH) is primarily caused by mutations of the bone morphogenetic protein (BMP) type-II receptor (BMPR2). Recent identification of mutations in the downstream mediator Smad-8 (gene, SMAD9) was surprising, because loss of Smad-8 function in canonical BMP signaling is largely compensated by Smad-1 and -5. We therefore hypothesized that noncanonical pathways may play an important role in PAH. To determine whether HPAH mutations disrupt noncanonical Smad-mediated microRNA (miR) processing. Expression of miR-21, miR-27a, and miR-100 was studied in pulmonary artery endothelial (PAEC) and pulmonary artery smooth muscle cells (PASMC) from explant lungs of patients with PAH. SMAD9 mutation completely abrogated miR induction, whereas canonical signaling was only reduced by one-third. miR-21 levels actually decreased, suggesting that residual canonical signaling uses up or degrades existing miR-21. BMPR2 mutations also led to loss of miR induction in two of three cases. HPAH cells proliferated faster than other PAH or controls. miR-21 and miR-27a each showed antiproliferative effects in PAEC and PASMC, and PAEC growth rate after BMP treatment correlated strongly with miR-21 fold-change. Overexpression of SMAD9 corrected miR processing and reversed the hyperproliferative phenotype. HPAH-associated mutations engender a primary defect in noncanonical miR processing, whereas canonical BMP signaling is partially maintained. Smad-8 is essential for this miR pathway and its loss was not complemented by Smad-1 and -5; this may represent the first nonredundant role for Smad-8. Induction of miR-21 and miR-27a may be a critical component of BMP-induced growth suppression, loss of which likely contributes to vascular cell proliferation in HPAH.