Blueberry Polyphenols Increase Nitric Oxide and Attenuate Angiotensin II-Induced Oxidative Stress and Inflammatory Signaling in Human Aortic Endothelial Cells
<p><b>Blueberry polyphenol extract (BPE) prevents the decrease in nitric oxide (NO) levels and the increase in superoxide production induced by angiotensin (Ang) II in human aortic endothelial cells (HAECs).</b> HAECs were treated with 200 µg/mL of BPE for 1 h then treated with 200 nM of Ang II for 12 h. NO levels were visualized (<b>A</b>) and quantified (<b>B</b>) after 30 min incubation with DAF-2DA. NO synthase (NOS) activity (<b>C</b>). ROS levels were determined after 30 min incubation with DHE (<b>D</b>) or H<sub>2</sub>DCFDA (<b>E</b>). Data are expressed as mean ± SD from three independent experiments. Values that do not share the same letter are significantly different from each other (<span class="html-italic">p</span> ≤ 0.05).</p> "> Figure 2
<p><b>Blueberry polyphenol extract (BPE) attenuates SAPK/JNK and p38 phosphorylation in angiotensin (Ang) II-treated human aortic endothelial cells (HAECs).</b> HAECs were treated with 200 µg/mL of BPE for 1 h then treated with 200 nM of Ang II for 12 h. Protein expression of phosphorylated and total SAPK/JNK (<b>A</b>,<b>B</b>), ERK1/2 (<b>C</b>,<b>D</b>), p38 (<b>E</b>,<b>F</b>), and Akt (<b>G</b>,<b>H</b>) were determined by Western blot. Quantification was performed using Image Lab (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Data are expressed as mean ± SD from three (SAPK/JNK), four (Akt) and five (ERK1/2 and p38) independent experiments. Values that do not share the same letter are significantly different from each other (<span class="html-italic">p</span> ≤ 0.05).</p> "> Figure 3
<p><b>Blueberry polyphenol extract (BPE) did not affect the expression of NADPH oxidases (NOX) in angiotensin (Ang) II-treated human aortic endothelial cells (HAECs).</b> HAECs were treated with 200 µg/mL of BPE for 1 h then treated with 200 nM of Ang II for 12 h. Protein expression of NOX1 (<b>A</b>,<b>B</b>), NOX2 (<b>C</b>,<b>D</b>), NOX4 (<b>E</b>,<b>F</b>), and NOX5 (<b>G</b>,<b>H</b>) were determined by Western blot. Quantification was performed using Image Lab (Bio-Rad Laboratories, Inc.). Data are expressed as mean ± SD from three (NOX1 and NOX4) and five (NOX2 and NOX5) independent experiments. Values that do not share the same letter are significantly different from each other (<span class="html-italic">p</span> ≤ 0.05).</p> "> Figure 4
<p><b>Blueberry polyphenol extract (BPE) increases the expression of antioxidant enzymes in angiotensin (Ang) II-treated human aortic endothelial cells (HAECs).</b> HAECs were treated with 200 µg/mL of BPE for 1 h then treated with 200 nM of Ang II for 12 h. Protein expression of SOD2 (<b>A</b>,<b>B</b>), SOD1 (<b>C</b>,<b>D</b>), GPx1 (<b>E</b>,<b>F</b>), CAT (<b>G</b>,<b>H</b>), and NQO1 (<b>I</b>,<b>J</b>) were determined by Western blot. Quantification was performed using Image Lab (Bio-Rad Laboratories, Inc.). Data are expressed as mean ± SD from seven (SOD1, SOD2, and GPx1) four (CAT) and six (NQO1) independent experiments. Values that do not share the same letter are significantly different from each other (<span class="html-italic">p</span> ≤ 0.05).</p> "> Figure 5
<p><b>Blueberry polyphenol extract (BPE) increases the expression of NRF2 and HO-1 while reducing NF-κB p65 phosphorylation in angiotensin (Ang) II-treated human aortic endothelial cells (HAECs).</b> HAECs were treated with 200 µg/mL of BPE for 1 h then treated with 200 nM of Ang II for 12 h. Protein expression of NRF2 (<b>A</b>,<b>B</b>), HO-1 (<b>C</b>,<b>D</b>), and NF-κB p65 (<b>E</b>,<b>F</b>) were determined by Western blot. Quantification was performed using Image Lab (Bio-Rad Laboratories, Inc.). Data are expressed as mean ± SD from nine (HO-1), and three (NRF2 and NF-κB) independent experiments. Values that do not share the same letter are significantly different from each other (<span class="html-italic">p</span> ≤ 0.05).</p> "> Figure 6
<p>Overall endothelial-dependent mechanisms by which blueberry polyphenols may attenuate hypertension. Upregulated renin–angiotensin–aldosterone system results in the increased synthesis of angiotensin (Ang) II, which causes vasoconstriction due to reduced endothelial-derived nitric oxide (NO). (A) Ang II binds to Ang II type-1 receptor (AT<sub>1</sub>R), which results in the activation of NADPH-oxidase (NOX)1. NOX1 synthesizes superoxide anions (O<sub>2</sub><sup>•−</sup>), which can react with NO, reducing NO bioavailability. (B) Blueberries may reverse this effect by increasing the synthesis of NO via increased endothelial NO synthase (eNOS) activity. (C) Mitogen-activated protein kinases (MAPKs), such as p38MAPK and stress-activated protein kinases (SAPK)/Jun amino-terminal kinases (JNK), are redox-sensitive kinases activated by upstream MAPK kinase kinase (MAPKKK). The phosphorylation of p38MAPK and SAPK/JNK expression was attenuated by blueberry polyphenols, suggesting reduced cellular oxidative stress. (D) Inhibitor of nuclear factor kappa B (IκB) kinase (IKK) is also a redox-sensitive kinase, which can undergo auto-phosphorylation upon interaction with reactive oxygen species (ROS) and is upstream of NF-κB. Following IKK phosphorylation, IκB is phosphorylated and the p65 subunit of NF-κB is then also phosphorylated. IκB then undergoes ubiquitin-dependent degradation, liberating NF-κB to translocate to the nucleus where it is involved in inflammatory transcription. Blueberries, however, reduced p65 phosphorylation, suggesting reduced IKK phosphorylation via reduced ROS. (E) These cytoprotective effects of blueberry polyphenols may be mediated by nuclear factor-erythroid factor 2-related factor 2 (NRF2), a master regulator of antioxidant enzymes. Kelch-like ECH-associated protein (KEAP)1 sequesters NRF2 in the cytosol and the entire complex undergoes ubiquitin-dependent degradation. However, conformational changes in KEAP1 prevent NRF2 binding, allowing NRF2 to translocate to the nucleus where it is involved in the transcription of antioxidant enzymes, NADPH dehydrogenase quinone (NQO)1 and superoxide dismutase (SOD)1, both of which can neutralize O<sub>2</sub><sup>•−</sup>. Blueberries increase cellular NRF2 concentration possibly via interaction with KEAP1, resulting in increased NQO1 and SOD1, overall reducing NOX1-mediated oxidative stress preventing NO neutralization via O<sub>2</sub><sup>•−</sup>.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Extraction of Blueberry Polyphenols
2.3. Total Polyphenol Content
2.4. Total Anthocyanin Content
- A = (A520–A700 nm) pH1.0 − (A520–A700 nm) pH4.5.
- MW (molecular weight) = 449.2 g/mol for cyanidin-3-glucoside.
- DF = dilution factor.
- 1 = pathlength in cm.
- ε = 26,900 molar extinction coefficient in L × mol−1 × cm−1 for cyanidin-3-glucoside.
- 103 = factor for conversion from g to mg
2.5. BPE Total Antioxidant Capacity
2.6. Cell Culture
2.7. Cell Viability
2.8. ROS Measurements
2.9. Intracellular NO
2.10. NOS Activity
2.11. Western Blot Analysis
2.12. Statistical Analysis
3. Results
3.1. Polyphenol Content of BPE
3.2. Effects of BPE on NO and ROS Levels in Ang II-Treated HAECs
3.3. BPE Attenuated the Phosphorylation of SAPK/JNK and p38MAPK in Ang II-Treated HAECs
3.4. BPE Did Not Attenuate Ang II-Induced Increase in NOX1 Expression in HAECs
3.5. BPE Increased the Expression of Antioxidant Enzymes in HAECs Treated with Ang II
3.6. BPE Increased the Expression of NRF2 and Attenuated Ang II-Induced Increase in NF-κB Expression in HAECs
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Total Polyphenol Content | Total Anthocyanin Content | Antioxidant Capacity (FRAP) |
---|---|---|
141.3 ± 3.4 µmol GAE/L | 105.3 ± 2.0 C3GE mg/L | 205.3 ± 4.7 µmol Fe2+/L |
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Najjar, R.S.; Mu, S.; Feresin, R.G. Blueberry Polyphenols Increase Nitric Oxide and Attenuate Angiotensin II-Induced Oxidative Stress and Inflammatory Signaling in Human Aortic Endothelial Cells. Antioxidants 2022, 11, 616. https://doi.org/10.3390/antiox11040616
Najjar RS, Mu S, Feresin RG. Blueberry Polyphenols Increase Nitric Oxide and Attenuate Angiotensin II-Induced Oxidative Stress and Inflammatory Signaling in Human Aortic Endothelial Cells. Antioxidants. 2022; 11(4):616. https://doi.org/10.3390/antiox11040616
Chicago/Turabian StyleNajjar, Rami S., Shengyu Mu, and Rafaela G. Feresin. 2022. "Blueberry Polyphenols Increase Nitric Oxide and Attenuate Angiotensin II-Induced Oxidative Stress and Inflammatory Signaling in Human Aortic Endothelial Cells" Antioxidants 11, no. 4: 616. https://doi.org/10.3390/antiox11040616