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miR‐223 a new signaling hub accounting for DNA damage signaling and STAT3 activation in pulmonary arterial hypertension (406.6)
Author(s) -
Vinck Jerome,
Ruffenach Gregoire,
Potus François,
Sandra BreuilsBonnet,
Provencher Steeve,
Bonnet Sebastien
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.406.6
Subject(s) - downregulation and upregulation , stat3 , cancer research , poly adp ribose polymerase , transcription factor , signal transduction , biology , dna damage , chemistry , microbiology and biotechnology , polymerase , dna , genetics , gene
Background: We reported that pulmonary arterial hypertension (PAH) is associated with an increased activation of Poly(ADP‐ribose) polymerase‐1 (PARP‐1) and the transcription factor STAT3 within the pulmonary arterial smooth muscle cells (PASMC). PARP‐1/STAT3 are common denominators to numerous pathways implicated in PAH including inflammation, Warburg effect; DNA repair; proliferation and apoptosis; thus PARP‐1/STAT3 activation can eventually leads to PAH. Despite extensive research PARP‐1/STAT3 activation mechanism remains elusive. Micro‐RNAs are non‐coding small RNA implicated in PAH etiology, in sillico analysis revealed that an interaction between the transcription factor CEBPα and miR‐233 is likely implicated in PARP‐1/STAT3 activation. We hypothesized that miR‐223 is downregulated in PAH contributing to PARP‐1/STAT3 activation. Methods and results: Using qRT‐PCR, we demonstrated that miR‐223 is significantly downregulated in Human PAH lungs, distal pulmonary arteries (<800μm) and cultured PAH‐PASMCs compare to control donors (n=3 to 5 patients). Downregulation of miR‐223 was associated with a significant downregulation at both mRNA (qRT‐PCR) and protein levels (immunoblot and immunofluorescence) of CEBPα, a transcription factor known to regulate miR‐223. Interestingly, the CEBPα‐dependent downregulation of miR‐223 was associated with PARP‐1 and STAT3 activation in PAH‐PASMC contributing to their prolifération. Conclusion: We provide preliminary evidences of the implication of a CEBPα/miR‐223 axis in the etiology of PAH, and its likely implication in the activation of PARP‐1/STAT3 signaling known to regulates PASMC proliferation and resistance to apoptosis. Therefore, CEBPα/miR‐223 represents a new avenue of investigation and a putative new therapeutic target for PAH.