Premium
Role for DNA repair signaling in coronary artery stenosis (1071.9)
Author(s) -
Meloche Jolyane,
Pflieger Aude,
Provencher Steeve,
Bonnet Sébastien
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.1071.9
Subject(s) - dna damage , dna repair , apoptosis , artery , poly adp ribose polymerase , cancer research , coronary arteries , stenosis , proliferating cell nuclear antigen , coronary artery disease , oxidative stress , microbiology and biotechnology , cell growth , biology , medicine , dna , biochemistry , polymerase
Coronary artery stenosis is a vascular disease characterized by sustained inflammation and oxidative stress, leading to DNA damage. Despite these detrimental conditions, coronary artery smooth muscle cells (CoASMC) show increased proliferation and suppressed apoptosis leading to luminal narrowing. PARP‐1 is a critical enzyme acting as DNA damage sensor by promoting either DNA repair or apoptosis depending on the amount of damage. Recent studies demonstrated the implication of the glycogen synthase 3 (GSK3) enzyme, which when inhibited, favors DNA repair (promoting cell survival and proliferation) and resistance to apoptosis (by promoting mitochondrial hyperpolarization). Thus, we hypothesized that increased DNA damage in coronary artery of patients with stenosis promotes PARP‐1 activation and GSK3 inhibition. In freshly isolated human CoASMC issued from control or stenosed arteries, we measured DNA damage, PARP‐1 expression and phosphorylated GSK3 protein levels. We demonstrated that CoASMC from stenosed arteries exhibit increased DNA damage, enhanced PARP‐1 expression and GSK3 inhibition. These cells also present mitochondrial membrane hyperpolarization and consequently show increased proliferation and suppressed apoptosis. Our study suggests an important role of DNA damage signaling and metabolism dysfunction in coronary stenosis and opens the door to new avenues of investigation and treatment. Grant Funding Source : Supported by CIHR grants