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Sci Rep. 2017 May 2;7(1):1334. doi: 10.1038/s41598-017-01392-1.

Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway.

Author information

1
Department of Experimental Medical Science, Lund University, Lund, Sweden.
2
Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
3
Department of Laboratory Medicine, Lund University, Lund, Sweden.
4
Department of Experimental Medical Science, Lund University, Lund, Sweden. karl.sward@med.lu.se.

Abstract

Hypertension is a dominating risk factor for cardiovascular disease. To characterize the genomic response to hypertension, we administered vehicle or angiotensin II to mice and performed gene expression analyses. AngII treatment resulted in a robust increase in blood pressure and altered expression of 235 genes in the aorta, including Gucy1a3 and Gucy1b3 which encode subunits of soluble guanylyl cyclase (sGC). Western blotting and immunohistochemistry confirmed repression of sGC associated with curtailed relaxation via sGC activation. Analysis of transcription factor binding motifs in promoters of differentially expressed genes identified enrichment of motifs for RBPJ, a component of the Notch signaling pathway, and the Notch coactivators FRYL and MAML2 were reduced. Gain and loss of function experiments demonstrated that JAG/NOTCH signaling controls sGC expression together with MAML2 and FRYL. Reduced expression of sGC, correlating with differential expression of MAML2, in stroke prone and spontaneously hypertensive rats was also seen, and RNA-Seq data demonstrated correlations between JAG1, NOTCH3, MAML2 and FRYL and the sGC subunits GUCY1A3 and GUCY1B3 in human coronary artery. Notch signaling thus provides a constitutive drive on expression of the major nitric oxide receptor (GUCY1A3/GUCY1B3) in arteries from mice, rats, and humans, and this control mechanism is disturbed in hypertension.

PMID:
28465505
PMCID:
PMC5430981
DOI:
10.1038/s41598-017-01392-1
[Indexed for MEDLINE]
Free PMC Article

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