Source: International Congress 2018 – Pathobiology of pulmonary hypertension
Disease area: Pulmonary vascular diseases

Abstract

Cleavage and polyadenylation is an important and regulated step in the maturation of mRNAs. Alternative polyadenylation (APA) is typically a shortening of the 3’UTR of affected gene by using a second polyadenylation signal. This shortening can remove regulation and can lead to increased expression of these mRNAs. APA induced by the depletion of the 25kDa subunit of cleavage factor I (CFIm25) has been shown to affect transcripts encoding for extracellular matrix (ECM) Proteins. This leads to the hypothesis that APA due to reduced CFIm25 expression could play a role in modulating ECM production of pulmonary vasculature in pulmonary hypertension (PH). Immunoblot and IHC staining of tissue sections show decreased CFIm25 levels in the pulmonary smooth muscle cells(PASMCs) of patients with PH compared to healthy lungs. Similar reduced expression has been seen in the hypoxia-sugen mouse model of PH. RNA-seq experiments in PASMCs treated with siRNA for CFIm25, revealed many transcripts that are significantly shortened, including an enrichment of ECM transcripts. Among these are Hyaluronan Synthase 2(HAS2), CD44 and LAMC1. This shortening was also seen in RNA extracted from human PH patients. Additionally HAS2 transcripts and Hyaluronan levels were increased in PASMCs of patients with PH. Transgenic depletion of CFIm25 in PASMCs in the hypoxia-sugen model led to increased symptoms while transgenic knockout of HAS2 in the same cells was protective in this model. These findings lead to the conclusion that CFIm25 depletion contributes to the development of PH through APA and subsequent up-regulation of ECM components.

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S. Collum, T. Weng (Tingting.Weng@uth.tmc.edu / UTHealth,Houston), A. Hernandez (Adriana.M.Hernandez@uth.tmc.edu / UTHealth,Houston), T. Mertens (Tinne.C.Mertens@uth.tmc.edu / UTHealth,Houston), N. Chen (Ning-Yuan.Chen@uth.tmc.edu / UTHealth,Houston), A. Guha (gashrith@houstonmethodist.org / Debakey Heart & Vascular Center,Houston), K. Youker (kayouker@houstonmethodist.org / Debakey Heart & Vascular Center,Houston), E. Wagner (ejwagner@UTMB.EDU / UTMB,Galveston), L. Han (Leng.Han@uth.tmc.edu / UTHealth,Houston), M. Blackburn (Michael.R.Blackburn@uth.tmc.edu / UTHealth,Houston), H. Karmouty-Quintana (Harry.Karmouty@uth.tmc.edu / UTHealth,Houston). LSC - 2018 - Alternative Polyadenylation(APA) modulates extracellular matrix deposition in pulmonary hypertension. 3922

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