Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8

KM Drake, D Zygmunt, L Mavrakis… - American journal of …, 2011 - atsjournals.org
KM Drake, D Zygmunt, L Mavrakis, P Harbor, L Wang, SA Comhair, SC Erzurum, MA Aldred
American journal of respiratory and critical care medicine, 2011atsjournals.org
Rationale: 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. Objectives: To determine whether HPAH mutations …
Rationale: 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.
Objectives: To determine whether HPAH mutations disrupt noncanonical Smad-mediated microRNA (miR) processing.
Methods: 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.
Measurements and Main Results: 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.
Conclusions: 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.
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