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17β-Estradiol nongenomically induces vascular endothelial H 2 S release by promoting phosphorylation of cystathionine γ-lyase

17β-Estradiol nongenomically induces vascular endothelial H 2 S release by promoting phosphorylation of cystathionine γ-lyase

Xingyan Xu, Qing Yan, Xiaoyun Liu, Ping Li, Xiaosa Li, Yiwen Chen, Tommaso Simoncini, Junxiu Liu, Dongxing Zhu, Xiaodong Fu

J Biol Chem. 2019 Oct 25;294(43):15577-15592.

PMID: 31439665

Abstract:

Estrogen exerts its cardiovascular protective role at least in part by regulating endothelial hydrogen sulfide (H2S) release, but the underlying mechanisms remain to be fully elucidated. Estrogen exerts genomic effects, i.e. those involving direct binding of the estrogen receptor (ER) to gene promoters in the nucleus, and nongenomic effects, mediated by interactions of the ER with other proteins. Here, using human umbilical vein endothelial cells (HUVECs), immunological detection, MS-based analyses, and cGMP and H2S assays, we show that 17β-estradiol (E2) rapidly enhances endothelial H2S release in a nongenomic manner. We found that E2 induces phosphorylation of cystathionine γ-lyase (CSE), the key enzyme in vascular endothelial H2S generation. Mechanistically, E2 enhanced the interaction of membrane ERα with the Gα subunit Gαi-2/3, which then transactivated particulate guanylate cyclase-A (pGC-A) to produce cGMP, thereby activating protein kinase G type I (PKG-I). We also found that PKG-Iβ, but not PKG-Iα, interacts with CSE, leading to its phosphorylation, and rapidly induces endothelial H2S release. Furthermore, we report that silencing of either CSE or pGC-A in mice attenuates E2-induced aorta vasodilation. These results provide detailed mechanistic insights into estrogen's nongenomic effects on vascular endothelial H2S release and advance our current understanding of the protective activities of estrogen in the cardiovascular system.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245694	Protein Kinase G Iβ human			Price

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