Article Cite This: J. Agric. Food Chem. 2019, 67, 7060−7072
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Protocatechuic Acid-Ameliorated Endothelial Oxidative Stress through Regulating Acetylation Level via CD36/AMPK Pathway Lin Han,†,‡ Qing Yang,§ Jia Li,† Feier Cheng,† Yao Zhang,† Yunlong Li,∥ and Min Wang*,† †
College of Food Science and Engineering, Northwest A&F University, Yangling 712100, P. R. China College of Biology and Food Engineering, Chongqing Three Gorges University, Chongqing 404100, P. R. China § College of Animal Science and Technology, Northwest A&F University, Yangling 712100, P. R. China ∥ Institute of Agricultural Products Processing, Shanxi Academy of Agriculture Sciences, Taiyuan 030006, P. R. China Downloaded via GUILFORD COLG on July 18, 2019 at 03:40:41 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
ABSTRACT: As one of the main metabolites of anthocyanin, protocatechuic acid (PCA) possesses strong antioxidant activity. In the present study, we explored the capacity of PCA on the alleviation of endothelial oxidative stress and investigated the underlying mechanisms using RNA sequencing (RNA-Seq). In comparison with palmitic acid (PA)-treated cells, PCA (100 μM) significantly decreased the generations of 3-nitrotyrosine (3-NT) and 8-hydroxydeoxyguanosine (8-OHdG) (0.82 ± 0.01 vs 1.16 ± 0.05 and 0.80 ± 0.01 vs 1.48 ± 0.15, respectively, p < 0.01), two biomarkers of oxidative damage, and restored the levels of nitric oxide (NO) (0.97 ± 0.04 vs 0.54 ± 0.02, p < 0.01) and mitochondrial membrane potential (MMP) (0.96 ± 0.03 vs 0.86 ± 0.02, p < 0.01) in human umbilical vein endothelial cells (HUVECs). PCA also obviously reduced the level of reactive oxygen species (ROS) (0.86 ± 0.15 vs 2.67 ± 0.09, p < 0.01) in aorta from high-fat diet (HFD)-fed mice. RNA-Seq and Western blot analysis indicated that PCA markedly reduced the expression of cluster of differentiation 36 (CD36), a membrane fatty acid transporter, and reduced the generations of adenosine triphosphate (ATP) and acetyl coenzyme A (Ac-CoA). These effects of PCA were associated with decreased level of acetylated-lysine and restored the activity of manganese-dependent superoxide dismutase (MnSOD) through reducing the generation of Ac-CoA or activating Sirt1 and Sirt3 via a CD36/AMPkinase (AMPK) dependent pathway. KEYWORDS: PCA, endothelial oxidative stress, CD36, AMPK, deacetylation
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INTRODUCTION In modern society, high-sugar and high-fat diets are commonly consumed in Occident and some Asian counties.1 However, this lifestyle causes many health problems, such as obesity, type 2 diabetes, and cardiovascular diseases (CVDs).2 Among these chronic diseases, CVDs have become the leading cause of mortality all over the world with an average death rate of 235 per 100 000 population,3 and lipid metabolism disorderinduced oxidative stress of vascular endothelium, namely, endothelial dysfunction, is a crucial event.4 High-fat diet provides an amount of fatty acids for humans, and palmitic acid (PA) is the most common saturated fatty acid that is positively correlated with the level of ROS or oxidative stress.5 As the β-oxidative product of PA, Ac-CoA provides acetyl to the proteins and increases the global levels of histone acetylation in various cell types.6 Acetylation is recognized as an important posttranslational modification of proteins, which influences the functions of many enzymes, including endogenous antioxidant enzymes.7 For example, acetylation at lysine 122, K53, and K89 of MnSOD inhibited its antioxidative activity, which led to an increase of mitochondrial superoxide and oxidative stress.8,9 Sirtuins (Sirts) are a universally conserved family containing seven proteins with NAD+-dependent deacetylase activity that play important roles in redox homeostasis, fat metabolism, transcriptional regulation, apoptosis, etc.10 Until now, Sirt1 and Sirt3 are two widely studied sirts with high activity of © 2019 American Chemical Society
deacetylation, as well as close relationships with oxidative stress. Previous reports indicated that Sirt1 enhanced the activities of antioxidant enzymes through deacetylating forkhead box O1 (FoxO1) or inhibited ROS generation via decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation.11−13 Sirt3 could directly deacetylate several critical lysine residues at 122, K53, and K89 sites of MnSOD and restore its antioxidative activity.8,9 AMPK, an energy sensor of a cell, was reported to promote the expression of nicotinamide phosphoribosyltransferase (NAMPT) and enhance its activity, subsequently restoring the level of NAD+ and increasing the activities of Sirts in vivo.14 As one of the main metabolites of anthocyanins, protocatechuic acid (PCA) is widely distributed in tea, buckwheat, grape, cauliflower, and chicory.15 Previous reports showed that PCA revealed strong antioxidant activity including free radical scavenging capacity and activation of endogenous antioxidant enzymes ability.16,17 Our previous study indicated that PCA promoted the expression of heme oxygenase 1 (HO1) and increased the activities of SOD and glutathione peroxidase 1 (GPx-1) through LKB1-AMPK-Nrf2 pathway in HUVECs.18 However, the detailed mechanisms about the Received: April 27, 2019 Accepted: June 4, 2019 Published: June 4, 2019 7060
DOI: 10.1021/acs.jafc.9b02647 J. Agric. Food Chem. 2019, 67, 7060−7072
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Journal of Agricultural and Food Chemistry
microscope (Olympus IX71, Tokyo, Japan), and the fluorescence intensity was calculated. Measurement of 3-NT and 8-OHdG. The levels of 3nitrotyrosine (3-NT) and 8-hydroxydeoxyguanosine (8-OHdG) were measured by using Human 3-NT and 8-OHdG ELISA kits (Catalog nos. JYM0780Hu and JYM0765Hu, respectively, Wuhan Colorful-Gene Biological Technology, Co. Ltd., Wuhan, China). After treatment with different concentrations (10, 50, and 100 μM) of PCA under PA (100 μM) for 24 h, cells were washed by PBS (0.0067 M, 0.1 μM sterile filtered) twice, 200 μL of radio immunoprecipitation assay (RIPA) lysis buffer (50 mM, pH 7.4, Tris, 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS and sodium vanadate, leupeptin, phenylmethanesulfonyl fluoride (PMSF)) (Xi’an Hat Biotechnology Co. Ltd., Xi’an, China) was added, and the cell lysates were collected and centrifuged (10 000 rpm for 10 min at 4 °C); then the supernatant was used to investigate the contents of 3NT and 8-OHdG according to the operation instructions. Data were presented as mean ± SD of three independent experiments. Lactate Dehydrogenase Leakage Assay. The lactate dehydrogenase (LDH) leakage was determined using Lactate Dehydrogenase Assay kit (Jiancheng, Nanjing, China). Briefly, cells plated in 6-well plates were preprotected with different concentrations (10, 50, and 100 μM) of PCA for 30 min and then coincubated with PA (100 μM) for another 24 h. The culture medium was collected and centrifuged (10 000 rpm for 10 min at 4 °C), and the supernatant was employed to determine the activity of LDH according to manufacturer’s instruction. The results were represented as percentage changes compared to the blank group with three independent experiments. Measurement of NO Release and Ac-CoA Content. The NO release assay was performed by using NO Detection kit (Jiancheng Bioengineering Institute, Nanjing, China), and the content of Ac-CoA was measured with Human Ac-CoA ELISA kit (Shanghai EnzymeLinked Biotechnology Co. Ltd., Shanghai, China). After treatment with PCA (100 μM) and stimulation with PA (100 μM) for 12 h, cell lysates were collected as described earlier and centrifuged (10 000 rpm for 10 min at 4 °C). The supernatant was used to assay the NO generation and Ac-CoA content according to the manufacturer’s instructions. Three replicates of each experiment were performed, and the levels of NO and Ac-CoA were represented as fold changes to blank group and U/μg·L, respectively. Measurement of Mitochondrial Membrane Potential. Mitochondrial Membrane Potential Assay kit with JC-1 (Beyotime, Nanjing, China) was employed to determine the mitochondrial membrane potential (MMP) according to our previous study with some modifications.21 At the end of treatment with PCA (100 μM) and PA (100 μM) for 6 h, cells were incubated with 1 mL of JC-1 for 20 min in dark and washed using JC-1 buffer solution twice. Analysis was performed at Ex/Em-525/590 nm using fluorescence inversion microscope (Olympus, Japan), and the fluorescence intensity was calculated by Image-Pro Plus 6.0 software with three independent experiments. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), an inhibitor of mitochondrial electron transfer chain, was used as a control. RNA Sequencing and Validation. Three groups including control group (CK), 100 μM PA-treated group (PA), and 100 μM PCA + PA cotreated group (Y100) were performed. After being treated for 12 h, cells were washed by PBS (0.0067 M, 0.1 μM sterile filtered) twice, and the RNA of each group was collected using TRIzol reagent (Life Technologies, Carlsbad, CA, U.S.A.). The following procedures were operated according to the description of Yang et al.19 Twenty significant differentially expressed genes (DEGs) were randomly chose to be validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method, and Table S1 exhibits the specific primers that were synthesized by Sangon Company (Shanghai, China) for the selected genes. Measurement of ATP and AMP. HPLC equipped with a reversed-phase C18 column (250 mm × 4.6 mm, 5.0 μm) and diode array detector (DAD) was used to determine the contents of ATP and AMP according to the method reported by Sellick et al. with some modifications.22 Briefly, after treatment for 12 h, cells were collected
regulations of PCA on the activation of AMPK and activities of antioxidant enzymes were still unclear. To the best of our knowledge, no studies have researched the effect of PCA on the activities of antioxidant enzymes from the perspective of deacetylation modification. In recent years, high-throughput RNA sequencing (RNA-Seq) was gradually used to research the effect of natural products on the gene expressions and their relationships.19 Therefore, in this study, we employed RNASeq to explore the upstream regulation mechanism of PCA on the activation of AMPK and preliminarily investigated the deacetylation of PCA and its effect on the activity of MnSOD via CD36/AMPK pathway.
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MATERIALS AND METHODS
Chemicals. PCA (98% by high-performance liquid chromatography (HPLC), CAS no. 99-50-3) and sulfo-N-succinimidyl oleate (SSO) (CAS no. 135661-44-8) were purchased from Yuanye Biotech. Co. (Shanghai, China) and Santa Cruz Biotech. (Dallas, TX, U.S.A.), respectively. Compound C (CC, purity >99%, Cat no. HY-13418) and Acadesine (AICAR) (Cat no. HY-13417) were purchased from MedChemExpress (Monmouth Junction, NJ, U.S.A.). These chemicals were dissolved in dimethyl sulfoxide (DMSO), diluted with phosphate-buffered saline (PBS) (0.0067 M, 0.1 μM sterile filtered), and finally added into the medium to reach corresponding concentrations (the final concentration of DMSO is 1600 DEGs were excavated between the three different treated groups, especially in CK vs PA and CK vs Y100 groups. However, PCA (100 μM) treatment revealed a mild effect on the gene expression, with only 43 DEGs compared to PAtreated group. KEGG analysis suggested that these DEGs were mainly enriched in metabolic pathway, cGMP-PKG signaling pathway, and cancer-related pathways. Among these DEGs, the gene of cd36 was discovered and aroused our interest because of its fatty acid transport function. As one member of the class B scavenger receptor family, CD36 is widely distributed in various types of cells, including endothelial cell, macrophage, adipocyte, and myocyte, which facilitates fatty acids uptake into high-affinity tissues.36 Overexpression of CD36 was correlated with lipid accumulation, steatosis, and metabolic dysfunction.1 We found that the expression of CD36 at RNA and protein levels significantly increased in PA-treated HUVECs or HFD-fed mice aorta, indicating that the longchain fatty acids uptake was also enhanced. However, PCA treatment significantly reduced the expression of CD36 and thereby inhibited the uptake of fatty acids. As is well-known to all, fatty acid could be metabolized to generate lots of Ac-CoA or ATP through mitochondrial β-oxidation and TCA. Thus, PCA significantly reduced the generations of ATP and Ac-CoA and increased the ratio of AMP/ATP through inhibiting CD36. Ac-CoA is a critical metabolic signaling molecule that regulates many key cellular processes, such as gene expression, autophagy, and energy metabolism, via influencing the activities of multiple enzymes.7 What is more, as an essential
Figure 7. Effect of PCA on the expression of CD36. Cells were incubated with difference concentrations (10, 50, or 100 μM) of PCA by adding PA (100 μM) for 12 h, and cellular lysates were collected and used for Western blotting. Data are calculated from three independently replicated experiments. (*) p < 0.05 and (**) p < 0.01 compared to the PA-treated group.
higher than that of other polyphenols (∼20−30 mg/day).15 Anthocyanins can be rapidly absorbed and metabolized to form various phenolic acids and aldehydes, including PCA, caffeic acid, ferulic acid, etc.31 As the main metabolite of anthocyanins, PCA has a high concentration in vivo with multiple health functions, such as antioxidant, anti-inflammatory, antihyperglycemic, and neuroprotective activities.15 Vitaglione et al. reported that, after consumption of 1 L of blood orange juice (containing 71 mg of cyanidine glucosides) by 6 healthy and fasting volunteers, the max concentration of PCA in the blood was high, up to 65.7 ± 0.10 μM.32 For these reasons, the doses of PCA used in our cellular and animal experiments were determined as 100 μM and 100 mg/kg, respectively. Accumulated evidence has shown that consumption of anthocyanins could alleviate high-fat diet-induced oxidative stress in vivo, which was probably associated with the antioxidant activity of PCA.33,34 In the present study, we found that 100 μM PCA treatment significantly decreased the generations of two biomarkers of oxidative damage, 3-NT
Figure 8. Effect of PCA on the level of acetyl-CoA and the ratio of AMP/ATP in HUVECs. Cells were treated for 12 h and collected for determination of the levels of acetyl-CoA, AMP, and ATP. Data are presented as mean ± SD of three independent experiments. (*) p < 0.05 and (**) p < 0.01 compared to the PA-treated group. 7068
DOI: 10.1021/acs.jafc.9b02647 J. Agric. Food Chem. 2019, 67, 7060−7072
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Figure 9. Effect of PCA or SSO on the expressions of phosphorylated AMPK, Sirt1, and Sirt3 in HUVECs. Cells were cultured with PCA or SSO for 12 h and then collected for Western blotting analysis. Data are calculated from three independently replicated experiments. (*) p < 0.05 and (**) p < 0.01 compared to the PA-treated group.
Figure 10. Effect of PCA or SSO on the lysine acetylation and MnSOD activity. Cells were stimulated by PA (100 μM) with or without PCA or SSO; after that, cellular lysates were collected for Western blotting analysis or centrifuged, and the supernatants were used to investigate the activity of MnSOD. Three independently replicated experiments are performed. (**) p < 0.01 compared to the PA-treated group.
functions including redox homeostasis, fat metabolism, transcriptional regulation, apoptosis, etc.10 Previous studies indicated that Sirt1 and Sirt3 were closely related with cellular oxidative stress via deacetylation, and the activities of the two Sirts were influenced by the phosphorylation level of AMPK.10 Sirt1 could increase the activities of antioxidant enzymes through deacetylating FoxO1 and reduce ROS generation via inhibiting the activity of NADPH oxidase.11−13 We have reported that D-fagomine could activate AMPK, increase the expression of Sirt1, promote mitochondrial synthesis, and alleviate oxidative stress in HUVECs through deacetylating PGC-1α.21 More importantly, Sirt3 directly deacetylated several critical lysine residues at 122, K53, and K89 sites of MnSOD and recovered its antioxidative activity.8,9 As observed in this study, PCA significantly activated AMPK via inhibiting CD36 and promoted the expressions of Sirt1 and Sirt3, thus
cofactor of acetylation, Ac-CoA provides acetyl group to the Nε amino group of lysine residues, which increases the global level of protein acetylation.6 Acetylation is recognized as an important posttranslational modification of proteins, which influences the functions of many enzymes (including endogenous antioxidant enzymes) by eliminating the positive charge or introducing steric hindrance.7 As has been reported, acetylation at lysine 122, K53, and K89 significantly decreased the activity of MnSOD and increased the oxidative stress in cells and mice.8,9 Our study found that PCA significantly reduced the generation of Ac-CoA through inhibiting CD36 and, subsequently, decreased the acetylation level of proteins in HUVECs and mice aorta, which was closely related with the recovery of MnSOD activity. Moreover, Sirt1 and Sirt3 are two important NAD+dependent deacetylases that regulate many physiological 7069
DOI: 10.1021/acs.jafc.9b02647 J. Agric. Food Chem. 2019, 67, 7060−7072
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Journal of Agricultural and Food Chemistry
Figure 11. Effect of PCA on the expression of (A) CD36, (B) p-AMPK, and (C) acetyl protein in mice aorta. Samples were treated and observed by confocal microscopy (scale bar, 20 μm). The fluorescence intensity was calculated, and data are presented as mean ± SD. (*) p < 0.05 and (**) p < 0.01 compared to the HFD group.
the antioxidant activity of PCA through its ability of acetylation regulation via CD36/AMPK pathway, and further experiments are required to further investigate the deacetylation of PCA and the effects on the activities of antioxidant enzymes.
decreasing the acetylation levels of proteins in HUVECs and aorta from HFD-fed mice, which was probably another pathway for PCA to restore the activity of MnSOD and exhibit its antioxidant activity. Met, a clinical antidiabetic agent, was reported to reduce the level of ROS and improve endothelial dysfunction through activating AMPK.23 The deacetylation effects of PCA by inhibiting the expression of CD36 in the aorta of HFD-fed mice were reproduced by the oral administration of Met (200 mg/kg), which further implicated the activation of AMPK in the effects of PCA. In summary, our study demonstrated that PCA could attenuate PA- or HFD-induced oxidative stress in HUVECs and aorta from HFD-fed mice via decreasing the acetylation level of proteins and restoring the antioxidant activity of MnSOD. Moreover, it was found that treatment with PCA significantly inhibited the expression of CD36 and reduced the generation of Ac-CoA or activated Sirt1 and Sirt3 via an AMPK-dependent pathway, which contributed to the deacetylation of PCA against lysine residues of proteins. Therefore, the present study provides a new angle to explain
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.9b02647. Validation of DEGs by qRT-PCR and primer sequences used for qRT-PCR validation (PDF)
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AUTHOR INFORMATION
Corresponding Author
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[email protected]. Tel.: +86-130-32938796. ORCID
Feier Cheng: 0000-0002-9471-7541 Min Wang: 0000-0002-8606-4309 7070
DOI: 10.1021/acs.jafc.9b02647 J. Agric. Food Chem. 2019, 67, 7060−7072
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This work was financially supported by the China Agriculture Research System (CARS-08-E2-01), Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN201801229), and Chongqing Natural Science Foundation Project (cstc2018jcyjAX026). Notes
The authors declare no competing financial interest.
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ABBREVIATIONS USED
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REFERENCES
PCA, protocatechuic acid; RNA-Seq, RNA sequencing; HUVECs, human umbilical vein endothelial cells; CVDs, cardiovascular diseases; PA, palmitic acid; ROS, reactive oxygen species; ATP, adenosine triphosphate; GSH, glutathione; Ac-CoA, acetyl coenzyme A; MnSOD, Mn superoxide dismutases; Sirts, sirtuins; FoxO1, forkhead box O1; NADPH, nicotinamide adenine dinucleotide phosphate; NAMPT, nicotinamide phosphoribosyltransferase; NAD, nicotinamide adenine dinucleotide; HO-1, heme oxygenase-1; GPx-1, glutathione peroxidase; AMPK, AMP-activated protein kinase; Nrf2, nuclear factor erythroid-derived factor 2-related factor 2; LKB1, liver kinase B1; SSO, sulfo-N-succinimidyl oleate; CC, compound C; CD36, cluster of differentiation 36; NFD, normal diet; HFD, high-fat diet; Met, metformin; DCFH-DA, 2′,7′-dichlorofluorescin diacetate; 3-NT, 3-nitrotyrosine; 8OHdG, 8-hydroxydeoxyguanosine; LDH, lactate dehydrogenase; MMP, mitochondrial membrane potential; DEGs, differentially expressed genes; DAD, diode array detector; CD31, cluster of differentiation 31; PGC-1α, peroxisome proliferatoractivated receptor-γ coactivator-1α; DAPI, 4′,6-diamidino-2phenylindole; PBS, phosphate-buffered saline; DMSO, dimethylsulfoxide
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