Baicalin alleviates hyperglycemia-induced endothelial impairment via Nrf2

in Journal of Endocrinology
Correspondence should be addressed to L Jin: jin_litai@126.com

*(G Chen and X Chen contributed equally to this work)

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Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine, which exhibits strong anti-inflammatory, anti-viral and anti-tumor activities. The present work was devoted to elucidate the molecular and cellular mechanisms underlying the protective effects of Baicalin against diabetes-induced oxidative damage, inflammation and endothelial dysfunction. Diabetic mice, induced by streptozotocin (STZ), were treated with intraperitoneal Baicalin injections. Human umbilical vein endothelial cells (HUVECs) were cultured either in normal glucose (NG, 5.5 mM) or high glucose (HG, 33 mM) medium in the presence or absence of Baicalin for 72 h. We observed an obvious inhibition of hyperglycemia-triggered oxidative damage and inflammation in HUVECs and diabetic aortal vasculature by Baicalin, along with restoration of hyperglycemia-impaired nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway activity. However, the protective effects of Baicalin almost completely abolished in HUVECs transduced with shRNA against Nrf2, but not with nonsense shRNA. Mechanistic studies demonstrated that HG decreased Akt and GSK3B phosphorylation, restrained nuclear export of Fyn and nuclear localization of Nrf2, blunted Nrf2 downstream target genes and subsequently induced oxidative stress in HUVECs. However, those destructive cascades were well prevented by Baicalin in HUVECs. Furthermore, LY294002 and ML385 (inhibitor of PI3K and Nrf2) attenuated Baicalin-mediated Nrf2 activation and the ability of facilitates angiogenesis in vivo and ex vivo. Taken together, the endothelial protective effect of Baicalin under hyperglycemia condition could be partly attributed to its role in downregulating reactive oxygen species (ROS) and inflammation via the Akt/GSK3B/Fyn-mediated Nrf2 activation.

 

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    Baicalin attenuates hyperglycemia-induced endothelial dysfunction both in vivo and in vitro. (A) Representative immunofluorescence with CD31 from C57BL/6 mice received sodium citrate buffer (pH 4.5) injections, STZ-induced diabetic mice in the presence or absence of DMSO injections and Baicalin-treated STZ-induced diabetic mice at aorta tissue sections. The red area represented endothelium and the nucleus was blue. Scale bars = 200 μm. (B) Quantification of the CD31-positive area in (A), values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs C57BL/6 mice; #P < 0.05 vs diabetic mice or vehicle-treated diabetic mice. (C) Representative confocal images of apoptosis in aortal vascular endothelium from C57BL/6 mice treated as indicated in (A). Scale bars = 40 μm. (D) The quantitative analysis of TUNEL+ cells in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs C57BL/6 mice; #P < 0.05 vs diabetic mice or vehicle treated diabetic mice. (E) Representative images of aortic rings from C57BL/6 mice cultured in different mediums containing NG (5.5 mM), HG (33 mM) alone or with Baicalin (50 μM) for 72 h, MAN (33 mM: 5.5 mM of glucose + 27.5 mM of D-mannitol) was served as the osmotic control for the HG. Scale bars = 200 μm. (F) Quantification of the number of sprouts in (E), values displayed are means ± s.e.m. of ten independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG. (G) Capillary-like tube formation was assessed by Matrigel angiogenesis assay in HUVECs. HUVECs were cultured either in NG or HG medium in the presence or absence of Baicalin (50 μM) for 72 h, MAN was served as the osmotic control for the HG. Scale bars = 300 μm. (H) Quantification of the tube length in (G), images of tube morphology were taken in six random microscopic fields per sample and values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG. (I) TUNEL assay of HUVECs treated as indicated in (G). The apoptotic cells were labeled with green, and nuclei were stained with DAPI (blue). Scale bars = 100 μm. (J) The quantitative analysis of TUNEL+ cells in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG. (K) Cell lysates of HUVECs were used to detect Bax, Bcl-2 as well as c-Caspase 3 protein levels by immunoblotting. (L and M) The quantitative analysis of each immunoblots, the results were normalized to HUVECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG.

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    Baicalin attenuates hyperglycemia-induced oxidative stress and inflammation in HUVECs via activating Nrf2-mediated exogenous antioxidant defenses both in vivo and in vitro. (A) Fluorescent images and quantitation of superoxide levels in HUVECs cultured either in NG or HG medium in the presence or absence of Baicalin (50 μM) for 72 h, MAN was served as the osmotic control for the HG. Superoxide was determined with the fluorescent indicator DHE, and the fluorescent intensity of DHE was observed with a computer-assisted microscope (EVOS, Thermo Fisher Scientific) Scale bars = 100 μm. (B) The quantitative analysis of fluorescent intensity in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG. (C) Representative confocal images of oxidative damage marker 3-NT in aortal vascular endothelium from C57BL/6 mice, diabetic mice, and intraperitoneal Baicalin (50 mg/kg/day) treated diabetic mice. The red area represented endothelium, the green area represents 3-NT positive staining and the nucleus was blue. Scale bars = 40 μm. (D) Quantification of the number of 3-NT staining in (C), values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs C57BL/6 mice; #P < 0.05 vs diabetic mice or vehicle treated diabetic mice. (E) Levels of the oxidative damage marker 3-NT in HUVECs treated with or without HG (33 mM) in the presence or absence of Baicalin (50 μM) for 72 h was detected by Western blot. MAN was served as the osmotic control for the HG. (F) The quantitative analysis of 3-NT protein immunoblots, the results were normalized to HUVECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs. NG or MAN; #P < 0.05 vs. HG. (G) Cytosolic (c-Nrf2) and nuclear (n-Nrf2) protein levels of Nrf2 and total (T-Nrf2) expression of Nrf2 were detected by Western blot, Which assay of HUVECs treated as indicated in (E). (H, I and J) The quantitative analysis of each immunoblots, the results were normalized to HUVECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG. (K) Nrf2 nuclear translocation was determined in fixed cells by immunofluorescent staining in HUVECs. The red area represented Nrf2 and the nucleus was blue. Scale bars = 20 μm.

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    Baicalin attenuates hyperglycemia-induced oxidative stress and inflammation. HUVECs cultured either in NG or HG medium in the presence or absence of Baicalin for 72 h, MAN was served as the osmotic control for the HG, NAC (2 mM) was pretreated for 2 h every day before Baicalin administration to evaluate the effect of Baicalin on the oxidative stress. (A, B, C, D, E and F) The mRNA expression and quantitation of Nrf2 downstream target genes were evaluated by sqRT-PCR. (G, H, I, J and K) The mRNA expression and quantitation of NF-κB downstream target genes were evaluated by sqRT-PCR. Two independent experiments were performed. Data shown in graphs represent the mean ± s.d. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG.

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    Baicalin activates Nrf2 via Akt/GSK3B/Fyn pathway in HUVECs. HUVECs were pretreated with or without LY294002 (10 μM) for 30 min and then exposed to HG (33 mM) for 72 h in the presence or absence of Baicalin (50 μM), MAN (33 mM: 5.5 mM of glucose + 27.5 mM of D-mannitol) was served as the osmotic control for the HG. (A) The phosphorylation of Akt and GSK3B, the nuclear translocation of Fyn (n-Fyn) and Nrf2 (n-Nrf2) were evaluated by Western blot. (B) The quantitative analysis of each immunoblots, the results were normalized to HUVECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; **P < 0.01 vs NG or MAN; #P < 0.05 vs HG; &P < 0.05 vs HG in the presence of Baicalin. (C and D) The mRNA expression and quantitation of Nrf2 downstream target genes were determined by sqRT-PCR. (E and F) The mRNA expression and quantitation of NF-κB downstream target genes were determined by sqRT-PCR. Two independent experiments were performed. Data shown in graphs represent the mean ± s.d. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG; &P < 0.05 vs HG in the presence of Baicalin.

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    Baicalin activates Nrf2 via Akt/GSK3B/Fyn pathway both in vivo and in vitro. (A) Representative images of aortic rings from C57BL/6 mice were pretreated with or without inhibitor LY294002 (10 μM) for 30 min and then exposed to HG (33 mM) in the presence or absence of Baicalin (50 μM). Scale bars = 200 μm. (B) Quantification of the number of sprouts in (A), values displayed are means ± s.e.m. of ten independent experiments. *P < 0.05 vs HG; #P < 0.05 vs HG in the presence of Baicalin. (C) Capillary-like tube formation was assessed by Matrigel angiogenesis assay in HUVECs. HUVECs were cultured with or without LY294002 (10 μM) and then exposed to HG (33 mM) medium in the presence or absence of Baicalin (50 μM) for 72 h. Scale bars = 300 μm. (D) Quantification of the tube length in (C), images of tube morphology were taken in six random microscopic fields per sample and values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs HG; #P < 0.05 vs HG in the presence of Baicalin. (E) TUNEL assay of HUVECs treated as indicated in (C). The apoptotic cells were labeled with green, and nuclei were stained with DAPI (blue). Scale bars = 100 μm. (F) The quantitative analysis of TUNEL+ cells in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs HG; #P < 0.05 vs HG in the presence of Baicalin. (G) Superoxide product test assay of HUVECs treated as indicated in (C), Superoxide was determined with the fluorescent indicator DHE, and the fluorescent intensity of DHE was observed with a computer-assisted microscope. Scale bars = 100 μm. (H) The quantitative analysis of fluorescent intensity in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs HG; #P < 0.05 vs HG in the presence of Baicalin. (I) Representative confocal images of apoptosis in aortal vascular endothelium from vehicle treated diabetic mice, and intraperitoneal Baicalin (50 mg/kg/day) treated diabetic mice in the presence or absence of LY294002 (5 mg/kg/day). Scale bars = 40 μm. (J) The quantitative analysis of TUNEL+ cells in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs diabetic mice; #P < 0.05 vs diabetic mice in the presence of Baicalin. (K) Representative confocal images of oxidative damage marker 3-NT in aortal vascular endothelium from diabetic mice treated as indicated in (I). The red area represented endothelium, the green area represent 3-NT positive staining and the nucleus was blue. Scale bars = 40 μm. (L) Quantification of the number of 3-NT staining in (K), values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs diabetic mice; #P < 0.05 vs diabetic mice in the presence of Baicalin.

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    Baicalin-mediated preservation of Akt/GSK3B/Fyn pathway was further confirmed in HAOECs. HAOECs were pretreated with or without LY294002 for 30 min and then exposed to HG for 72 h in the presence or absence of Baicalin, MAN was served as the osmotic control for the HG. (A) The phosphorylation of Akt and GSK3B, the nuclear translocation of n-Fyn and n-Nrf2 were evaluated by Western blot. (B) The quantitative analysis of each immunoblots, the results were normalized to HAOECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG; &P < 0.05 vs HG in the presence of Baicalin. (C and D) The expression and quantitation of Nrf2 downstream target genes were evaluated by sqRT-PCR. The results were normalized to HAOECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG; &P < 0.05 vs HG in the presence of Baicalin. (E and F) The mRNA expression and quantitation of NF-κB downstream target genes were determined by sqRT-PCR. The results were normalized to HAOECs exposed to NG, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs NG or MAN; #P < 0.05 vs HG; &P < 0.05 vs HG in the presence of Baicalin. (G) Nrf2 nuclear translocation was determined in fixed cells by immunofluorescent staining in HAOECs. The red area represented Nrf2 and the nucleus was blue. Scale bars = 20 μm.

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    Knockdown of Nrf2 impairs the protective effects of Baicalin in HUVECs. (A) Protein expression of Nrf2 in HUVECs after transfecting with Nrf2 shRNA adenoviral vectors for 72 h assayed by Western blot to verify the efficacy of Nrf2 shRNA. (B) The quantitative analysis of Nrf2 immunoblots, the results were normalized to HUVECs transfected Ad-scramble, values displayed are means ± s.e.m. of six independent experiments. **P < 0.01 vs HUVECs transfected Ad-scramble. (C) HUVECs were transduced with adenoviruses harboring sh-Nrf2 (Ad-sh-Nrf2) and a scrambled sequence (Ad-scramble) respectively. After transduction, HUVECs were cultured either in MAN or HG medium in the presence or absence of Baicalin for 72 h. Protein expression of nuclear accumulation of Nrf2 in HUVECs after transfecting with adenoviruses assayed by Western blot. (D) The quantitative analysis of nuclear accumulation of Nrf2 immunoblots, the results were normalized to HUVECs transfected Ad-scramble expose to MAN. (E) Levels of the oxidative damage marker 3-NT in HUVECs was detected by Western blot. Which assay of HUVECs treated as indicated in (C). (F) The quantitative analysis of 3-NT protein immunoblots, the results were normalized to HUVECs transfected Ad-scramble. (G, H, I, J, K and L) The mRNA expression and quantitation of Nrf2 downstream target genes were determined by sqRT-PCR. Which assay of HUVECs treated as indicated in (C), the results were normalized to HUVECs transfected Ad-scramble. (M, N, O, P and Q) The mRNA expression and quantitation of NF-κB downstream target genes were determined by sqRT-PCR. Which assay of HUVECs treated as indicated in (C), the results were normalized to HUVECs transfected Ad-scramble. Data shown in graphs (C, D, E, F, G, H, I, J, K, L, M, N, O, P and Q) represent the means ± s.e.m. of six independent experiments. *P < 0.05 vs HUVECs transfected Ad-scramble expose to MAN; #P < 0.05 vs HUVECs transfected Ad-scramble expose to HG; &P < 0.05 vs HUVECs transfected Ad-scramble expose to HG in the presence Baicalin.

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    Knockdown or inhibitor of Nrf2 impairs the protective effects of Baicalin. (A) Capillary-like tube formation was assessed by Matrigel angiogenesis assay in HUVECs. HUVECs were transfected with or without adenoviral containing Nrf2 shRNA (Ad-sh-Nrf2) or scramble shRNA (Ad-scramble) and then exposed to HG medium in the presence or absence of Baicalin for 72 h. Scale bars = 300 μm. (B) Quantification of the tube length in (A), images of tube morphology were taken in six random microscopic fields per sample and values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs Ad-scramble HUVECs; #P < 0.05 vs Ad-scramble HUVECs in the presence of Baicalin. (C) TUNEL assay of HUVECs treated as indicated in (A). The apoptotic cells were labeled with green, and nuclei were stained with DAPI (blue). Scale bars = 100 μm. (D) The quantitative analysis of TUNEL+ cells in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs Ad-scramble HUVECs HG; #P < 0.05 vs Ad-scramble HUVECs in the presence of Baicalin. (E) Superoxide product test assay of HUVECs treated as indicated in (A), Superoxide was determined with the fluorescent indicator DHE, and the fluorescent intensity of DHE was observed with a computer-assisted microscope. Scale bars = 100 μm. (F) The quantitative analysis of fluorescent intensity in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs Ad-scramble HUVECs HG; #P < 0.05 vs Ad-scramble HUVECs HG in the presence of Baicalin. (G) Representative images of aortic rings from diabetic mice were pretreated with or without Nrf2 inhibitor ML385 and Baicalin, then cultured with HG in the presence or absence of ML385 and Baicalin. Scale bars = 200 μm. (H) Quantification of the number of sprouts in (G), values displayed are means ± s.e.m. of ten independent experiments. *P < 0.05 vs vehicle treated diabetic mice; #P < 0.05 vs diabetic mice in the presence of Baicalin. (I) Representative confocal images of apoptosis in aortal vascular endothelium from vehicle treated diabetic mice, and intraperitoneal Baicalin treated diabetic mice in the presence or absence of ML385. Scale bars = 40 μm. (J) The quantitative analysis of TUNEL+ cells in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs. vehicle treated diabetic mice; #P < 0.05 vs diabetic mice in the presence of Baicalin. (K) Representative confocal images of oxidative damage marker 3-NT in aortal vascular endothelium from diabetic mice treated indicated in (I). The red area represented endothelium, the green area represent 3-NT positive staining and the nucleus was blue. Scale bars = 40 μm. (L) Quantification of the number of 3-NT staining in (K), values displayed are means ± s.e.m. of eight independent experiments. *P < 0.05 vs vehicle treated diabetic mice; #P < 0.05 vs diabetic mice in the presence of Baicalin.

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    Nrf2 effects on the downstream of Akt/GSK3B/Fyn pathway. HUVECs were transduced with adenoviruses harboring sh-Nrf2 (Ad-sh-Nrf2) and a scrambled sequence (Ad-scramble) respectively. After transduction, HUVECs were cultured either in MAN or HG medium in the presence or absence of Baicalin for 72 h. (A, B, C, D and E) The protein expression and quantitative analysis of phosphorylation of Akt and GSK3B, the nuclear translocation of Fyn (n-Fyn) and Nrf2 (n-Nrf2) were evaluated by Western blot. The results were normalized to HUVECs transfected Ad-scramble expose to MAN, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs respective MAN in Ad-scramble-HUVECs or Ad-sh-Nrf2-HUVECs; #P < 0.05 vs respective HG in Ad-scramble-HUVECs or Ad-sh-Nrf2-HUVECs. (F, G, H, I, J and K) The mRNA expression and quantitation of Nrf2 downstream target genes were determined by sqRT-PCR. The results were normalized to HUVECs transfected Ad-scramble expose to MAN, values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs HUVECs transfected Ad-scramble expose to MAN; #P < 0.05 vs HUVECs transfected Ad-scramble expose to HG; &P < 0.05 vs Ad-scramble-HUVECs with the same treatment.

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    Baicalin alleviates hyperglycemia-induced endothelial impairment by downregulating oxidative damage via Nrf2 pathway. Schematic illustration of the protective effects of Baicalin on HUVECs under HG conditions. HG decreases expression of Nrf2 in HUVECs and induces oxidative stress, which impairs the survival and angiogenic function of HUVECs. Under HG conditions co-treatment with Baicalin improves HUVECs survival and function predominantly by Nrf2 activation mediated by increasing phosphorylation of Akt and GSK3B and inhibiting Fyn-mediated export of nuclear Nrf2. CAT indicates catalase; HO1, heme oxygenase 1; NQO1, NAD(P)H dehydrogenase (quinone 1); ROS, reactive oxygen species. A full color version of this figure is available at https://doi.org/10.1530/JOE-18-0457.

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