The histone demethylase Jarid1b mediates angiotensin II-induced endothelial dysfunction by controlling the 3'UTR of soluble epoxide hydrolase

Abstract

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 (AngII) could be inferred. This hypothesis was tested using Jarid1b knockout mice and the inhibitor PBIT.

Methods: Mice or aortic segments were treated with AngII 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 DetaNONOate 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 AngII. This effect was not a consequence of altered nitrite oxide availability but accompanied by a loss of the inflammatory response to AngII. As Jarid1b mainly inhibits gene expression, an indirect effect should account for this observation. AngII induced the soluble epoxide hydrolase (sEH), which degrades anti-inflammatory lipids, and thus promotes inflammation. Knockout or inhibition of Jarid1b prevented the AngII-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 AngII by stabilizing sEH expression. Jarid1b inhibition might be an option for future therapeutics against cardiovascular dysfunction.

Keywords: Jarid1B; RNA stability; soluble epoxide hydrolase; vessel tone.