Critical Promoter Region for Statin-Induced Human Endothelial Nitric Oxide Synthase (eNOS) Transcription in EA.hy926 Cells

Mashimo, Yoichi; Ishikawa, Takahiro; Numakura, Maiko; Kinoshita, Makoto; Teramoto, Tamio

doi:10.5551/jat.15388

Cited by 3 publications

(2 citation statements)

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“…33 The discrepancy between the effects of atorvastatin and resveratrol in GATA2 deficiency BOEC may be due to their effect at different positions of the promoter sequence. Atorvastatin increases eNOS mRNA by enhancing the activity of transcription factors that bind the eNOS promoter in the 5' region, 32 including the transcription factor c-Jun/AP-1 15 which was in fact significantly increased by this drug in both healthy control and GATA2-mutated BOEC. Differently, resveratrol enhances the activity of transcription factors that bind the eNOS promoter in the proximal 263 bp region 33 that involves the GATA2 binding site (254-279 bp).…”

Section: A B Cmentioning

confidence: 96%

“…BOEC from healthy controls and from GATA2-deficient patients at passage 5 were seeded in 24-well plates (150×10 3 cells/well) in serum-free EBM2 medium. Cells were incubated with atorvastatin at a concentration of 50 μM, 32 or with resveratrol 40 μM, 33 or with their vehicle (dimethyl sulfoxide [DMSO]) for 24 hours (h) in serum-free medium. DMSO final concentration never exceeded 0.5%.…”

Section: Treatment Of Blood Outgrowth Endothelial Cells With Enos Ind...mentioning

confidence: 99%

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Germline <i>GATA2</i> variant disrupting endothelial eNOS function and angiogenesis can be restored by c-Jun/AP-1 upregulation

et al. 2021

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GATA2 is a transcription factor with key roles in hematopoiesis. Germline GATA2 gene variants have been associated with several inherited and acquired hematologic disorders, including myelodysplastic syndromes. Among the spectrum of GATA2 deficiency-associated manifestations thrombosis has been reported in 25% of patients, but the mechanisms are unknown. GATA2 was shown to be involved in endothelial nitric oxide synthase (eNOS) regulation and vascular development. We assessed eNOS expression and angiogenesis in patients with GATA2-deficiency. Platelets and blood outgrowth endothelial cells (BOEC) from GATA2-variant carriers showed impaired NO-production and reduction of eNOS mRNA and protein expression and of eNOS activity. GATA2 binding to the eNOS gene was impaired in BOEC from GATA2-deficiency patients, differently from control BOEC. GATA2-deficiency BOEC showed also defective angiogenesis, which was completely restored by treatment with the NO-donor S-nitroso-N-acetylpenicillamine (SNAP). Atorvastatin, but not resveratrol, largely restored eNOS expression, NO biosynthesis and neoangiogenesis in GATA2-deficient BOEC by a mechanism involving increased expression of the eNOS transcription factor AP-1/c-JUN, replacing GATA2 when the latter is inactive. Our results unravel a possible thrombogenic mechanism of GATA2 mutations, definitely establish the regulation of eNOS by GATA2 in endothelial cells and show that endothelial angiogenesis is strictly dependent on the eNOS/NO axis. Given the ability of atorvastatin to restore NO production and angiogenesis by GATA2-deficient endothelial cells, the preventive effect of atorvastatin on thrombotic events and possibly on other clinical manifestations of the syndrome related to deranged angiogenesis should be explored in patients with GATA2-deficiency in an ad hoc designed clinical trial.

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Section: A B Cmentioning

confidence: 96%

Section: Treatment Of Blood Outgrowth Endothelial Cells With Enos Ind...mentioning

confidence: 99%