Novel Treatment of Hypertension by Specifically Targeting E2F for Restoration of Endothelial Dihydrofolate Reductase and eNOS Function Under Oxidative Stress-Reference-Cited by-同舟云学术

Novel Treatment of Hypertension by Specifically Targeting E2F for Restoration of Endothelial Dihydrofolate Reductase and eNOS Function Under Oxidative Stress

Published:2019-01 Issue:1 Volume:73 Page:179-189
ISSN:0194-911X
Container-title:Hypertension
language:en
Short-container-title:Hypertension

Author:

Li Hong¹²³,Li Qiang¹²,Zhang Yixuan¹²,Liu Wenting⁴,Gu Bo¹²,Narumi Taro¹²,Siu Kin Lung¹²,Youn Ji Youn¹²,Liu Peiqing³,Yang Xia⁴,Cai Hua¹²

Affiliation:

1. From the Division of Molecular Medicine, Department of Anesthesiology, Cardiovascular Research Laboratories (H.L., Q.L., Y.Z., B.G., T.N., K.L.S., J.Y.Y., H.C.), David Geffen School of Medicine, University of California, Los Angeles

2. Division of Cardiology, Department of Medicine, Cardiovascular Research Laboratories (H.L., Q.L., Y.Z., B.G., T.N., K.L.S., J.Y.Y., H.C.), David Geffen School of Medicine, University of California, Los Angeles

3. Department of Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China (H.L., P.L.).

4. Department of Integrative Biology and Physiology (W.L., X.Y.), David Geffen School of Medicine, University of California, Los Angeles

Abstract

We have shown that hydrogen peroxide (H 2 O 2 ) downregulates tetrahydrobiopterin salvage enzyme DHFR (dihydrofolate reductase) to result in eNOS (endothelial NO synthase) uncoupling and elevated blood pressure. Here, we aimed to delineate molecular mechanisms underlying H 2 O 2 downregulation of endothelial DHFR by examining transcriptional pathways hypothesized to modulate DHFR expression and effects on blood pressure regulation of targeting these novel mechanisms. H 2 O 2 dose and time dependently attenuated DHFR mRNA and protein expression and enzymatic activity in endothelial cells. Deletion of E2F-binding sites, but not those of Sp1 (specificity protein 1), abolished H 2 O 2 attenuation of DHFR promoter activity. Overexpression of E2F1/2/3a activated DHFR promoter at baseline and alleviated the inhibitory effect of H 2 O 2 on DHFR promoter activity. H 2 O 2 treatment diminished mRNA and protein expression of E2F1/2/3a, whereas overexpression of E2F isoforms increased DHFR protein levels. Chromatin immunoprecipitation assay indicated direct binding of E2F1/2/3a to the DHFR promoter, which was weakened by H 2 O 2 . E2F1 RNA interference attenuated DHFR protein levels, whereas its overexpression elevated tetrahydrobiopterin levels and tetrahydrobiopterin/dihydrobiopterin ratios in vitro and in vivo. In Ang II (angiotensin II)–infused mice, adenovirus-mediated overexpression of E2F1 markedly abrogated blood pressure to control levels, by restoring endothelial DHFR function to improve NO bioavailability and vasorelaxation. Bioinformatic analyses confirmed a positive correlation between E2F1 and DHFR in human endothelial cells and arteries, and downregulation of both by oxidized phospholipids. In summary, endothelial DHFR is downregulated by H 2 O 2 transcriptionally via an E2F-dependent mechanism, and that specifically targeting E2F1/2/3a to restore DHFR and eNOS function may serve as a novel therapeutic option for the treatment of hypertension.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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