NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia

Choi, Sang Zin; Kim, Ji Aee; Na, Hye Young; Park, Seonghee; Han, Ki Hwan; Kim, Young Ju; Suh, Suk Hyo

doi:10.1016/j.freeradbiomed.2012.12.009

Cited by 33 publications

(32 citation statements)

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“…3,4 Furthermore, we have reported that K Ca 3.1 downregulation contributes to endothelial dysfunction in the animal model of FD, Gla-knockout mice, 5 and patients with preeclampsia. 6 The density of membrane proteins in the plasma membrane is determined by a balance between forward trafficking from the endoplasmic reticulum (ER), endocytosis, and recycling/ degradation. 7,8 Recent studies demonstrate that various K + channel proteins undergo endocytosis and degradation, that is, the ATP-sensitive K + channel, 9 or K Ca 3.1.…”

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confidence: 99%

“…3 Subsequently, the gel was dried under vacuum and exposed to film. 4 5 PI(3)P mass strip assay 6 Extraction and detection of PI(3)P were performed with a PI(3)P Mass Strip Kit (K-3600; 7 Echelon Biosciences Inc., Salt Lake City, UT), according to the manufacturer's instruction. After 8 extraction of neutral and acidic lipids by phase split step, the organic (lower) phase was 9 transferred and dried in a vacuum dryer.…”

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Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K _Ca 3.1 in Fabry Disease

Choi

Kim

et al. 2014

ATVB

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Objective— Globotriaosylceramide (Gb3) induces K Ca 3.1 downregulation in Fabry disease (FD). We investigated whether Gb3 induces K Ca 3.1 endocytosis and degradation. Approach and Results— K Ca 3.1, especially plasma membrane–localized K Ca 3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells (MAECs) and human umbilical vein endothelial cells. Gb3-induced K Ca 3.1 downregulation was prevented by lysosomal inhibitors but not by a proteosomal inhibitor. Endoplasmic reticulum stress–inducing agents did not induce K Ca 3.1 downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from age-matched wild-type mice, those from aged α-galactosidase A (Gla)-knockout mice, an animal model of FD, showed downregulated K Ca 3.1 expression and upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 expression. In contrast, no significant difference was found in early endosome antigen 1 and lysosomal-associated membrane protein 2 expression between young Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was translocated close to the cell border and clathrin knockdown recovered K Ca 3.1 expression. Rab5, an effector of early endosome antigen 1, was upregulated, and Rab5 knockdown restored K Ca 3.1 expression, the current, and endothelium-dependent relaxation. Conclusions —Gb3 accelerates the endocytosis and lysosomal degradation of endothelial K Ca 3.1 via a clathrin-dependent process, leading to endothelial dysfunction in FD.

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Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K _Ca 3.1 in Fabry Disease

Choi

Kim

et al. 2014

ATVB

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“…In our previous studies, we reported that K Ca 3.1 is upregulated by H 2 O 2 and downregulated by superoxide (Choi et al ., 2013a,b), suggesting the possibility of endothelial K Ca 3.1 upregulation by H 2 O 2 in aged wild‐type and young CerS2 null MAECs. Thus, we examined K Ca 3.1 levels in aged wild‐type and young CerS2 null MAECs.…”

Section: Resultsmentioning

confidence: 99%

“…An increase in blood pressure has been reported in K Ca 3.1 knockout mice (Si et al ., 2006), and we have previously suggested that K Ca 3.1 downregulation is a cause of endothelial dysfunction in Fabry disease (Park et al ., 2011). In addition, we reported that superoxide generated from ECs downregulates K Ca 3.1, resulting in endothelial dysfunction in preeclampsia (Choi et al ., 2013a). In contrast, H 2 O 2 upregulates K Ca 3.1 via an ERK‐mediated pathway (Choi et al ., 2013a,b).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, we reported that superoxide generated from ECs downregulates K Ca 3.1, resulting in endothelial dysfunction in preeclampsia (Choi et al ., 2013a). In contrast, H 2 O 2 upregulates K Ca 3.1 via an ERK‐mediated pathway (Choi et al ., 2013a,b). Thus, ROS affect endothelial function by modulating endothelial K Ca 3.1 expression.…”

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confidence: 99%

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K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Choi

Kim

et al. 2016

Aging Cell

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SummaryEndothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa3.1, which contributes to EDR, is upregulated by H2O2. We investigated whether KCa3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H2O2 levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and KCa3.1 upregulation. Catalase/GPX1 double knockout (catalase−/−/GPX1−/−) upregulated KCa3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− MAECs. However, KCa3.1 activation‐induced, NG‐nitro‐l‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2O2 and thereby upregulate KCa3.1 expression and function via a H2O2/Fyn‐mediated pathway. Altogether, enhanced KCa3.1 activity may compensate for decreased NO signaling during vascular aging.

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Dietary Supplement with Tribulus terrestris L. Extract Exhibits Protective Effects on Ischemic Stroke Rats

Guo,

Yang,

Wang

et al. 2023

Molecular Nutrition Food Res

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ScopeAmong herbal dietary supplements, the extract of Tribulus terrestris L. (TT) has been used as a commercially registered product in multiple studies. The previous studies demonstrate the protective effect of gross saponins of TT (GSTTF) on ischemic stroke. However, the mechanism by which GSTTF protects against ischemic stroke is still unclear.Methods and resultsThe study applies molecular biology and unbiased transcriptomics to explore the pathways and targets underlying the therapeutic impact of GSTTF in treating ischemic stroke. The mRNA of brain tissues from different groups is analyzed using a transcriptomics method. The data reveal that treatment with GSTTF significantly reduces elevated CRP, IL‐6, and Ca2+ levels induced by middle cerebral artery occlusion (MCAO). A total of 61 differentially expressed genes (DEGs) are identified, GSTTF is found to effectively reverse the abnormal mRNA expression levels in rat brain tissues affected by ischemic stroke models. These positive effects of GSTTF are likely achieved through the suppression of calcium ion and the MyD88/IKK/NF‐κB signaling pathway.ConclusionsThis study uncovers the mechanisms behind the efficacy of GSTTF in treating ischemic stroke, which not only expands its potential medicinal applications but also confirmed its potential as a dietary supplement.

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NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia

Cited by 33 publications

References 43 publications

Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K _Ca 3.1 in Fabry Disease

Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K _Ca 3.1 in Fabry Disease

K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Dietary Supplement with Tribulus terrestris L. Extract Exhibits Protective Effects on Ischemic Stroke Rats

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NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia

Cited by 33 publications

References 43 publications

Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K Ca 3.1 in Fabry Disease

Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K Ca 3.1 in Fabry Disease

K Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Dietary Supplement with Tribulus terrestris L. Extract Exhibits Protective Effects on Ischemic Stroke Rats

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Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K _Ca 3.1 in Fabry Disease

Globotriaosylceramide Induces Lysosomal Degradation of Endothelial K _Ca 3.1 in Fabry Disease

K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress