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Expression of endothelin type B receptors (EDNRB) on smooth muscle cells is controlled by ternary complex factors and the actin cytoskeleton
Author(s) -
Krawczyk Katarzyna Karina,
Skovsted Gry Freja,
Perisic Ljubica,
Rippe Catarina,
Dreier Rasmus,
Berg Jais Oliver,
Lykkesfeldt Jens,
Hedin Ulf,
Swärd Karl
Publication year - 2018
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.2018.32.1_supplement.lb283
Subject(s) - receptor , myocardin , gene isoform , microbiology and biotechnology , endothelin receptor , endocrinology , agonist , calponin , activator (genetics) , medicine , messenger rna , chemistry , biology , actin , gene expression , biochemistry , gene , serum response factor
Endothelin signaling plays an important role in physiology and disease and one of the endothelin receptors, the type B receptor (ET B or EDNRB), is known to be highly plastic, being upregulated in smooth muscle cells by arterial injury and following organ culture in vitro . Herein, we hypothesized that this transcriptional plasticity may arise in part because EDNRB is controlled by ternary complex factors and by the myocardin family coactivator MKL2. In line with this hypothesis we found significant correlations between the ternary complex factors ELK3, FLI1 and EDNRB, and between MKL2 and EDNRB at the mRNA level in human arteries. Overexpression of MKL2 in human coronary artery smooth muscle cells (HCASMC) led to a 30‐ fold induction of EDNRB, and this effect was antagonized by myocardin (MYOCD) which also correlated negatively with EDNRB at the tissue level. Overexpression of ELK3 and FLI1 induced expression of EDNRB, whereas the expression of classical smooth muscle markers was reduced. Depolymerization of actin using latrunculin B (LatB) increased EDNRB on both mRNA and protein levels, and increased calcium responses on stimulation with the ET B ‐selective agonist sarafotoxin 6c (S6c) and endothelin 1 (ET‐1). Pretreatment with LatB in organ culture increased S6c and ET‐1‐induced contraction. We also found that ROCK inhibition using Y27632 induced EDNRB expression, and that the effect of LatB is antagonized by MAP‐kinase inhibition. Transcript‐specific primers and promoter reporter assays showed that the EDNRB_2 isoform is regulated by LatB in HCASMC. We finally demonstrate that the mRNA level of EDNRB is increased in rat carotid lesions and human carotid plaques, and that ELK3/FLI1 induction closely parallels EDNRB induction. In all, these studies uncover transcriptional control mechanisms for the endothelin type B receptor (EDNRB) that may explain its plasticity and could be targeted for therapy. Support or Funding Information This study was supported by grants from the Medical Faculty and The Royal Physiographic Society. KKK was supported by Marie Curie ITN Small Artery Remodelling of European Union. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .