Open AccessMDA ‐5 activation by cytoplasmic double‐stranded RNA impairs endothelial function and aggravates atherosclerosis
Author(s) -
Asdonk Tobias,
Steinmetz Martin,
Krogmann Alexander,
Ströcker Christine,
Lahrmann Catharina,
Motz Inga,
PaulKrahe Kathrin,
Flender Anna,
Schmitz Theresa,
Barchet Winfried,
Hartmann Gunther,
Nickenig Georg,
Zimmer Sebastian
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12864
Subject(s) - endothelial dysfunction , stimulation , endothelial stem cell , receptor , endothelium , biology , microbiology and biotechnology , chemistry , endocrinology , immunology , biochemistry , in vitro
Recent studies have highlighted the relevance of viral nucleic acid immunorecognition by pattern recognition receptors in atherogenesis. Melanoma differentiation associated gene 5 ( MDA ‐5) belongs to the intracellular retinoic acid inducible gene‐I like receptors and its activation promotes pro‐inflammatory mechanisms. Here, we studied the effect of MDA ‐5 stimulation in vascular biology. To gain insights into MDA ‐5 dependent effects on endothelial function, cultured human coronary artery endothelial cells ( HCAEC ) were transfected with the synthetic MDA ‐5 agonist poly IC (long double‐stranded RNA ). Human coronary endothelial cell expressed MDA ‐5 and reacted with receptor up‐regulation upon stimulation. Reactive oxygen species formation, apoptosis and the release of pro‐inflammatory cytokines was enhanced, whereas migration was significantly reduced in response to MDA ‐5 stimulation. To test these effects in vivo , wild‐type mice were transfected with 32.5 μg poly IC /Jet PEI or polyA/Jet PEI as control every other day for 7 days. In poly IC ‐treated wild‐type mice, endothelium‐dependent vasodilation and re‐endothelialization was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticles and circulating endothelial progenitor cells significantly elevated compared to controls. Importantly, these effects could be abrogated by MDA ‐5 deficiency in vivo . Finally, chronic MDA ‐5 stimulation in Apolipoprotein E/toll‐like receptor 3 ( TLR 3) double ‐ deficient (ApoE −/− / TLR 3 −/− ) mice‐enhanced atherosclerotic plaque formation. This study demonstrates that MDA ‐5 stimulation leads to endothelial dysfunction, and has the potential to aggravate atherosclerotic plaque burden in murine atherosclerosis. Thus, the spectrum of relevant innate immune receptors in vascular diseases and atherogenesis might not be restricted to TLR s but also encompasses the group of RLR s including MDA ‐5.