The MiR-130/301 Family Controls Cellular Survival in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a deadly vascular disease characterized by multiple disparate molecular pathways controlling vasoconstriction and hyperproliferation throughout the pulmonary vasculature. Importantly, the selection and proliferation of hardier pulmonary endothelial cells in PH may describe the origins of the anti-apoptotic and hyperproliferative phenotypes characterizing severe PH pathogenesis. However, the importance of cellular survival in mediating intercellular transfer of regulatory factors during PH progression has yet to be clearly defined. MicroRNAs (miRNAs) may coordinately regulate PH progression, but their integrative functions have been difficult to describe with conventional methods. Recently, using a network-based bioinformatics approach, we identified the miR-130/301 family as a master regulator governing pulmonary vascular proliferation as well as vasoconstriction and vessel stiffening in PH through repression of its direct target gene PPARγ. In this study, we additionally identify miR-130/301 as a regulator of cellular survival and show that the dysregulation of miR-130/301 in PH increases apoptotic activity in pulmonary arterial endothelial cells. Furthermore, we identify NCOA3 and PTEN as direct targets of miR-130/301 through which this miRNA family may control apoptotic signaling in the pulmonary vasculature. Our observations provide critical insight into the systems-level regulation of both cellular survival and proliferation by the miR-130/301 family in PH pathogenesis. Specifically, this model establishes a mechanistic framework describing the importance of miR-130/301 in the initiating apoptotic events of PH development. Moreover, our study suggests broad propositions for miRNA-based therapeutics for treating PH and further endorses the application of in silico network theory to decipher the combinatorial molecular origins of complex diseases such as PH.