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The histone demethylase Jarid1b mediates angiotensin II‐induced endothelial dysfunction by controlling the 3′UTR of soluble epoxide hydrolase
Author(s) -
Vasconez Andrea E.,
Janetzko Patrick,
Oo James A.,
PflügerMüller Beatrice,
Ratiu Corina,
Gu Lunda,
Helin Kristian,
Geisslinger Gerd,
Fleming Ingrid,
Schröder Katrin,
Fork Christian,
Brandes Ralf P.,
Leisegang Matthias S.
Publication year - 2019
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13168
Subject(s) - epoxide hydrolase 2 , demethylase , chemistry , angiotensin ii , endothelial dysfunction , histone , biochemistry , endocrinology , biology , enzyme , gene , receptor
Aim The histone demethylase Jarid1b limits gene expression by removing the active methyl mark from histone3 lysine4 at gene promoter regions. A vascular function of Jarid1b is unknown, but a vasoprotective function to inflammatory and hypertrophic stimuli, like angiotensin II (Ang II ) could be inferred. This hypothesis was tested using Jarid1b knockout mice and the inhibitor PBIT . Methods Mice or aortic segments were treated with Ang II to induce endothelial dysfunction. Aortae from WT and Jarid1b knockout were studied in organ chambers and endothelium‐dependent dilator responses to acetylcholine and endothelium‐independent responses to Deta NONO ate were recorded after pre‐constriction with phenylephrine in the presence or absence of the NO ‐synthase inhibitor nitro‐L‐arginine. Molecular mechanisms were investigated with chromatin immunoprecipitation, RNA ‐Seq, RNA ‐3′‐adaptor‐ligation, actinomycin D and RNA ‐immunoprecipitation. Results Knockout or inhibition of Jarid1b prevented the development of endothelial dysfunction in response to Ang II . This effect was not a consequence of altered nitrite oxide availability but accompanied by a loss of the inflammatory response to Ang II . As Jarid1b mainly inhibits gene expression, an indirect effect should account for this observation. Ang II induced the soluble epoxide hydrolase ( sEH ), which degrades anti‐inflammatory lipids, and thus promotes inflammation. Knockout or inhibition of Jarid1b prevented the Ang II ‐mediated sEH induction. Mechanistically, Jarid1b maintained the length of the 3′untranslated region of the sEH mRNA , thereby increasing its stability and thus sEH protein expression. Loss of Jarid1b activity therefore resulted in sEH mRNA destabilization. Conclusion Jarid1b contributes to the pro‐inflammatory effects of Ang II by stabilizing sEH expression. Jarid1b inhibition might be an option for future therapeutics against cardiovascular dysfunction.