Details

Autor(en) / Beteiligte

• Gao, Fei
• Hayashi, Yujiro
• Saravanaperumal, Siva Arumugam
• Gajdos, Gabriella B
• Syed, Sabriya A
• Bhagwate, Aditya V
• Ye, Zhenqing
• Zhong, Jian
• Zhang, Yuebo
• Choi, Egan L
• Kvasha, Sergiy M
• Kaur, Jagneet
• Paradise, Brooke D
• Cheng, Liang
• Simone, Brandon W
• Wright, Alec M
• Kellogg, Todd A
• Kendrick, Michael L
• McKenzie, Travis J
• Sun, Zhifu
• Yan, Huihuang
• Yu, Chuanhe
• Bharucha, Adil E
• Linden, David R
• Lee, Jeong-Heon
• Ordog, Tamas

Titel

Hypoxia-Inducible Factor 1α Stabilization Restores Epigenetic Control of Nitric Oxide Synthase 1 Expression and Reverses Gastroparesis in Female Diabetic Mice

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2023-12, Vol.165 (6), p.1458-1474

Ort / Verlag

United States

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Although depletion of neuronal nitric oxide synthase (NOS1)-expressing neurons contributes to gastroparesis, stimulating nitrergic signaling is not an effective therapy. We investigated whether hypoxia-inducible factor 1α (HIF1A), which is activated by high O consumption in central neurons, is a Nos1 transcription factor in enteric neurons and whether stabilizing HIF1A reverses gastroparesis. Mice with streptozotocin-induced diabetes, human and mouse tissues, NOS1 mouse neuroblastoma cells, and isolated nitrergic neurons were studied. Gastric emptying of solids and volumes were determined by breath test and single-photon emission computed tomography, respectively. Gene expression was analyzed by RNA-sequencing, microarrays, immunoblotting, and immunofluorescence. Epigenetic assays included chromatin immunoprecipitation sequencing (13 targets), chromosome conformation capture sequencing, and reporter assays. Mechanistic studies used Cre-mediated recombination, RNA interference, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated epigenome editing. HIF1A signaling from physiological intracellular hypoxia was active in mouse and human NOS1 myenteric neurons but reduced in diabetes. Deleting Hif1a in Nos1-expressing neurons reduced NOS1 protein by 50% to 92% and delayed gastric emptying of solids in female but not male mice. Stabilizing HIF1A with roxadustat (FG-4592), which is approved for human use, restored NOS1 and reversed gastroparesis in female diabetic mice. In nitrergic neurons, HIF1A up-regulated Nos1 transcription by binding and activating proximal and distal cis-regulatory elements, including newly discovered super-enhancers, facilitating RNA polymerase loading and pause-release, and by recruiting cohesin to loop anchors to alter chromosome topology. Pharmacologic HIF1A stabilization is a novel, translatable approach to restoring nitrergic signaling and treating diabetic gastroparesis. The newly recognized effects of HIF1A on chromosome topology may provide insights into physioxia- and ischemia-related organ function.