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Tytuł:
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Antenatal Dexamethasone Exposure Impairs the High-Conductance Ca Channels via Epigenetic Alteration at Gene Promoter in Male Offspring.
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Autorzy:
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Xu T; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Zhao M; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Li H; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Zhou X; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Liu B; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Sun M; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Xu Z; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
Gao Q; First Hospital of Soochow University, Institute for Fetology, Suzhou, China.
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Źródło:
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Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2020 Nov; Vol. 40 (11), pp. e284-e295. Date of Electronic Publication: 2020 Sep 24.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
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MeSH Terms:
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DNA Methylation*
Epigenesis, Genetic*
Prenatal Exposure Delayed Effects*
Promoter Regions, Genetic*
Dexamethasone/*toxicity
Glucocorticoids/*toxicity
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/*genetics
Large-Conductance Calcium-Activated Potassium Channel beta Subunits/*genetics
Mesenteric Arteries/*metabolism
Action Potentials ; Animals ; Dexamethasone/administration & dosage ; Female ; Glucocorticoids/administration & dosage ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism ; Large-Conductance Calcium-Activated Potassium Channel beta Subunits/metabolism ; Male ; Maternal Exposure ; Mesenteric Arteries/physiopathology ; Pregnancy ; Rats, Sprague-Dawley ; Vasodilation
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Contributed Indexing:
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Keywords: adult; electrophysiology; glucocorticoids; mesenteric arteries; risk factor
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Substance Nomenclature:
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0 (Glucocorticoids)
0 (KCNMB1 protein, rat)
0 (Kcnma1 protein, rat)
0 (Large-Conductance Calcium-Activated Potassium Channel alpha Subunits)
0 (Large-Conductance Calcium-Activated Potassium Channel beta Subunits)
7S5I7G3JQL (Dexamethasone)
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Entry Date(s):
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Date Created: 20200924 Date Completed: 20201214 Latest Revision: 20201214
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Update Code:
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20240105
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DOI:
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10.1161/ATVBAHA.120.314905
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PMID:
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32967457
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Objective: Antenatal exposure to glucocorticoids increases cardiovascular risks related to vascular dysfunctions in offspring, although underlying mechanisms are still unknown. As an important vascular mediator, high-conductance Ca 2+ -activated K + channels (BK) plays an essential role in determining vascular tone. Long-term effects of antenatal glucocorticoids on BK in offspring are largely unknown. This study examined the effects and mechanisms of antenatal exposure to clinically relevant doses of glucocorticoids on vascular BK in offspring. Approach and Results: Pregnant Sprague-Dawley rats received synthetic glucocorticoids dexamethasone or vehicle during the last week of pregnancy. Vascular functions, cellular electrophysiology, target gene expression, and promoter methylation were examined in mesenteric arteries of male offspring (gestational day 21 [fetus] and postnatal day 120 [adult offspring]). Antenatal dexamethasone exposure impaired BK activators-mediated relaxation and reduced whole-cell BK currents in mesenteric arteries. Antenatal dexamethasone exposure did not alter Ca 2+ /voltage-sensitivity of BK but downregulated the expressions of BK α and β1 subunits in both fetal and adult mesenteric arteries. In addition, increased promoter methylations within BKα and BKβ1 were compatible with reduced expressions of the 2 genes.
Conclusions: Our findings showed a profound and long-term impact of antenatal dexamethasone exposure on vascular BK via an altered epigenetic pattern from fetal stage to adulthood, advancing understanding of prolonged adverse effects and mechanisms of antenatal glucocorticoids exposure on vascular health in offspring.