Blueberry Anthocyanin-Enriched Extracts Attenuate Fine Particulate

Dec 5, 2016 - Blueberry anthocyanin-enriched extracts (BAE) at three doses (0.5, 1.0, and 2.0 g/kg) were administered by oral gavage to rats exposed t...
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Blueberry Anthocyanin-Enriched Extracts Attenuate Fine Particulate Matter (PM2.5)‑Induced Cardiovascular Dysfunction Ziyu Wang,†,‡ Wei Pang,‡ Congcong He,‡ Yibo Li,‡ Yugang Jiang,*,‡ and Changjiang Guo*,†,‡ †

School of Public Health, Guangxi Medical University, Nanning 530021, China Department of Nutrition, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China

‡

S Supporting Information *

ABSTRACT: Blueberry anthocyanin-enriched extracts (BAE) at three doses (0.5, 1.0, and 2.0 g/kg) were administered by oral gavage to rats exposed to 10 mg/kg fine particulate matter (PM2.5) three times a week. A positive control group was exposed to PM2.5 without BAE treatment. We analyzed heart rate (HR), electrocardiogram (ECG), and histopathology, and biomarkers of cardiovascular system injuries, systemic inflammation, oxidative stress, endothelial function, and apoptosis. Results indicated that BAE, particularly at 1.0 g/kg, improved ECG and decreased cytokine levels in PM2.5-exposed rats. These changes were accompanied by an increase in interleukin 10 levels and superoxide dismutase activity in heart tissue and Bcl-2 protein expression, as well as a decrease in interleukin 6, malondialdehyde, endothelin 1, and angiotensin II levels and a reduction in Bax protein expression. This study demonstrates that BAE at certain doses can protect the cardiovascular system from PM2.5-induced damage. KEYWORDS: fine particulate matter, blueberry anthocyanin-enriched extracts, cardiovascular disease, inflammation, oxidative stress

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INTRODUCTION Cardiovascular disease (CVD) is an important cause of morbidity and mortality worldwide. It has been predicted that the proportion of CVD-related deaths to worldwide deaths would increase from 28% in 1990 to 31.5% in 2020.1 Growing epidemiological evidence has demonstrated that both shortand long-term exposure to particulate matter (PM), and especially to fine particulate matter (PM2.5), is involved in the induction, progression, and worsening of CVD.2 A metaanalysis conducted by Mustafic et al. revealed a significant association between short-term (up to 7 days) exposure to CO, NO2, SO2, PM2.5, and PM10 and increased risk of myocardial infarction.3 A time-series study (3 years) in Beijing reported that with each cumulative 10 μg/m3 increase in PM2.5 concentration, ischemic heart disease (IHD) morbidity increased by 0.27% and IHD mortality increased by 0.25% on the same day.4 Inflammation and oxidative stress have been considered major mechanisms underlying PM2.5-induced CVD. In particular, exposure to PM2.5 may activate inflammatory and pro-oxidative pathways in the lungs, including cytokine release, expression of proinflammatory cytokines, release of reactive oxygen species (ROS), production of endothelins, recruitment of macrophages, and a hypercoagulable and prothrombotic state.5 Some researchers have speculated that PM-induced pulmonary inflammation elicits a systemic inflammatory response, which

may, in turn, activates hemostatic pathways, impairs vascular function, and accelerates atherosclerosis.6 Oxidative stress mediated by ROS could trigger cellular pathological processes, including apoptosis, inflammation, and proliferation owing to the activation of redox-sensitive signal transduction pathways.7 One study showed that PM2.5-induced oxidative stress increased the expression of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) in a human umbilical vein cell line.8 Mossman reported that oxidative stress played an important role in PM-induced pulmonary inflammation.9 A recent study found that vitamin E and omega-3 fatty acids could restrict PM2.5-induced inflammation and oxidative stress in vascular endothelial cells.10 The ability of anthocyanins to reduce inflammation and oxidative stress, while exerting positive effects on endothelial function and preventing cardiomyocyte apoptosis, has been extensively studied in CVD models. Blueberry anthocyanin-enriched extracts (BAE) attenuated cyclophosphamide-induced cardiac injury, a result attributable to their antioxidant and anti-inflammatory properties.11 Adding fresh blueberries (80 g/kg) to a high-cholesterol diet for 75 days resulted in attenuation of oxidative stress and cholesterol accumulation in the aorta and liver of guinea pigs.12 In addition, many studies showed that anthocyanins increased endothelium-dependent vasodilation in hypercholesterolemic individuals and attenuated α-adrenergic-induced vasoconstriction in spontaneously hypertensive rats (SHR) via induction of the NO−cGMP signaling pathway.13,14 Moreover, anthocyanins protected endothelium dilation in SHR by altering the aortic glycosaminoglycan profile.15 Skemiene et al. found that

Table 1. Main Elemental Composition and Concentration of Fine Particulate Matter element

concentration (%)

element

concentration (%)

Zn

59.31

Cr

0.97

Pb

21.95

Cd

0.54

Cu

13.16

Ni

0.51

As

5.13

Hg

0.07

© XXXX American Chemical Society

Received: Revised: Accepted: Published: A

October 19, 2016 December 5, 2016 December 5, 2016 December 5, 2016 DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

BAE Oral Gavage. Blueberry extracts were purchased from Daxinganling Lingonberry Organic Foodstuffs Co, Ltd. (Haebing, China); the anthocyanidin content was 11.6%, predominantly cyanidin 3-O-β-glucoside and peonidin 3-O-β-glucoside, determined by high performance liquid chromatography (HPLC).18 Blueberry anthocyanins were dissolved in double-distilled water prior to the experiment. Rats were divided randomly into five groups (n = 8 per group): control, PM2.5-exposed group, PM2.5 + BAE (0.5 g/kg) group, PM2.5 + BAE (1.0 g/kg) group, and PM2.5 + BAE (2.0 g/kg) group. Rats in the three BAE-treated groups received BAE by gavage at the indicated doses daily for 5 weeks; rats in the other two groups were given the same volume (5.0 mL/kg) of distilled water. PM2.5 Exposure. PM2.5 sampled with an intelligent flow air total suspended particulate sampler (Wuhan Tianhong Instrument Co. Ltd., Hubei, China) was collected onto glass fiber filters from October 22, 2014 to January 31, 2015 in Tianjin, China. PM2.5 suspensions were diluted to 10 mg/1.5 mL with sterilized 0.9% saline and sonicated for 30 min using a KH 2200 DE sonicator (Kunshan He Chuang Sonicator Ltd., Jiangsu, China) before instillation. Rats in the PM2.5exposed group and the three BAE-treated groups were instilled with the PM2.5 suspension (10 mg/kg), whereas those in the control group were instilled with the same volume of physiological saline on the sixth week. Instillation was performed every 2 days using a nonsurgical intratracheal instillation method, while the rats received BAE by gavage. The rats had free access to food and water when not treated. Electrocardiographic Data Acquisition. Twenty-four hours after the third exposure, electrocardiogram (ECG) morphology was recorded for 10 min with subcutaneous electrodes of the standard II configuration (right arm, right leg, and left leg) using a BL-420E biological and functional experimental system (Chengdu Taimeng Technology Co., Ltd., Siquan, China) when the heart rate (HR) of the anesthetized rats stabilized. Blood Collection and Assays. After ECG recordings, rats were sacrificed by drawing blood from the descending abdominal aorta using disposable sterile syringes. The blood from each rat was divided into two parts and collected in EDTA-treated and non-EDTA-treated tubes. The blood was centrifuged (1510g at 4 °C) for 10 min. The plasma collected in the EDTA-treated tubes and the serum

Figure 1. Blueberry anthocyanin-enriched extracts (BAE) attenuated PM2.5-induced increase in heart rate. All data represent the mean ± SEM; #p < 0.05 compared to the control group.

20 μM anthocyanin cyanidin-3-glucoside (Cy3G) could block ischemia-induced apoptosis in the perfused heart.16 In addition, anthocyanins from fermented berry beverages have positive effects on type-2 diabetes therapy by modulating DPP-IV and its substrate GLP-1.17 Even though blueberry anthocyanins have been shown to exhibit antioxidant and anti-inflammatory properties, data on the effects of anthocyanins on PM2.5-induced oxidative stress and inflammation are sparse. The aim of this study was to evaluate the effects of BAE on PM2.5-induced cardiovascular dysfunction and to explore the underlying mechanisms.

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MATERIALS AND METHODS

Animals. Forty male Sprague−Dawley (SD) rats (8 weeks old) weighing 180−220 g were obtained from the Tianjin Institute of Health and Environmental Medicine (Tianjin, China). The rats were housed in an animal facility and left to acclimatize for 1 week. All animals used in this study had free access to food and water and were kept under controlled environmental conditions (12-h light/dark cycle; temperature approximately 22 ± 2 °C).

Figure 2. Blueberry anthocyanin-enriched extracts (BAE) attenuated PM2.5-induced electrocardiogram changes: (A) control group; (B) PM2.5 exposure group; (C) PM2.5 + BAE (0.5 g/kg) group; (D) PM2.5 + BAE (1.0 g/kg) group; (E) PM2.5 + BAE (2.0 g/kg) group. B

DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Figure 3. Blueberry anthocyanin-enriched extracts (BAE) attenuated a PM2.5-induced increase in myocardial enzymes: (A) lactate dehydrogenase (LDH) activity in serum, (B) LDH activity in the heart, (C) creatine kinase (CK) activity in serum, (D) CK activity in the heart, (E) creatine kinase isoenzyme MB (CK-MB) activity in serum, and (F) CK-MB activity in the heart. All data represent the mean ± SEM; #p < 0.05 compared to the control group, *p < 0.05 compared to the PM2.5 exposure group, &p < 0.05 compared to the PM2.5 + BAE (1.0 g/kg) group. collected in the non-EDTA-treated tubes were stored at −80 °C until analyses. Levels of creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), and C-reactive protein (CRP) in the serum were measured using a random access clinical analyzer (Glamour 3000, USA). Lactate dehydrogenase (LDH) and superoxide dismutase (SOD) activities, as well as malondialdehyde (MDA) concentration in the serum were assayed by commercial colorimetric assay kits (Nanjing Jiancheng Bioengineering Institute, Jiangsu, China). Interleukin 6 (IL-6) and interleukin 10 (IL-10) levels in the serum were measured using radioimmunoassays (China Isotope Company, Beijing, China). The concentrations of angiotensin II and endothelin 1 (ET-1) in the plasma were determined using ELISA kits (Shanghai Tongwei Bioengineering Institute, Shanghai, China). Preparation of Heart Homogenates. The heart was excised, washed in saline, and briefly blotted on filter paper. Hearts were

divided into three parts: The cardiac apex was fixed in 10% formalin for histopathological examination; the left heart was used for Western blot analysis; the right heart was homogenized for biochemical analysis. The right part of the heart was separated and homogenized in ice-cold saline using a G50 motor-driven tissue grinder (Coyote Bioscience Technology Limited Company, Beijing, China). The homogenate (10%) was centrifuged at 1762g for 10 min at 4 °C. The supernatant was collected and stored at −80 °C for further use. Levels of CK, CK-MB, LDH, MDA, and SOD were measured by the same methods used for the serum. Western Blotting. Protein concentrations were determined using a bicinchoninic acid (BCA) protein assay kit (Sangon Biotech, Shanghai, China). Samples were mixed with the loading buffer and boiled for 5 min. Samples containing 40 μg of proteins were separated on 10% SDS-PAGE and transferred to poly(vinylidene C

DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Figure 4. Blueberry anthocyanin-enriched extracts (BAE) attenuated PM2.5-induced endothelial system dysfunction: (A) endothelin 1 (ET-1) concentration in plasma and (B) angiotension II concentration in the plasma. All data represent the mean ± SEM; #p < 0.05 compared to the control group, *p < 0.05 compared to the PM2.5 exposure group. difluoride) (PVDF) membranes (Millipore, Grand Island, NY, USA). The membrane was blocked with 15% skimmed milk powder in Tris-buffered saline containing 0.1% Tween-20 (TBST) overnight at 4 °C. Next, the samples were reacted with rabbit antiBax antibody and rabbit anti-Bcl-2 antibody (1:1,000 dilution, Cell Signaling Technology, Danvers, MA, USA) overnight at 4 °C, and then incubated with goat horseradish peroxidase-conjugated anti-rabbit IgG (1:7,000 dilution, Cell Signaling Technology) for 1 h at 37 °C. Antibody binding was detected by chemiluminescence staining using an ECL detection kit (Advansta, USA), and the film was subjected to ImageMaster VDS (Pharmacia, Wikipedia, Sweden). The density of the protein bands was quantified by Totallab software and Quantity One software (Bio-Rad, USA). All data were normalized to the endogenous reference protein GAPDH. Histopathological Examination. The aorta was excised, washed in saline, and briefly blotted on filter paper. The cardiac apex and aorta were fixed in buffered 10% formalin solution for 48 h. After fixation, the tissues were embedded in paraffin and processed according to routine histological procedures. Five micrometer-thick sections were prepared and stained with hematoxylin and eosin (H&E). A pathologist blinded to the treatments performed the histopathological examination using an optical microscope (200×). Statistical Analysis. Results are expressed as means ± standard deviation (SD). Independent samples t test was applied for statistical comparisons between the control and PM2.5-exposed groups. The differences between the PM2.5-exposed group and BAE-treated groups were analyzed by one-way analysis of variance (ANOVA) with Dunnett’s or LSD post hoc test. Probability values of p < 0.05 were considered statistically significant. SPSS 21.0 for Windows was used for statistical analyses.

Figure 5. Blueberry anthocyanin-enriched extracts (BAE) attenuated PM2.5-induced systemic inflammation: (A) interleukin 6 concentration in serum, (B) interleukin 10 concentration in serum, and (C) C-reactive protein (CRP) concentration in serum. All data represent the mean ± SEM; #p < 0.05 compared to the control group, *p < 0.05 compared to the PM2.5 exposure group, &p < 0.05 compared to the PM2.5 + BAE (1.0 g/kg) group.

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RESULTS Main Elemental Concentrations in PM2.5. The main elemental concentrations in PM2.5 are shown in Table 1. Concentrations of Zn, Pb, and Cu were much higher than those of other metals. HR Analyses. Figure 1 depicts HR measurements in all experimental groups. HR decreased significantly in the PM2.5-exposed group. In contrast, HR increased in the PM2.5 + BAE (1.0 g/kg) group; however, this increase did not reach statistical significance. ECG Changes. Normal sinus rhythm was observed in most rats of the control group at the end of the experiment (Figure 2A). However, abnormal ECG changes were observed in the other experimental groups, such as ST segment elevation in rats of the PM2.5 and PM2.5 + BAE (0.5 g/kg) groups (Figure 2B,C). In the PM2.5 + BAE (1.0 g/kg) group, most rats were similar to controls (Figure 2D). The ECG of rats in the D

DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Figure 6. Blueberry anthocyanin-enriched extracts (BAE) attenuated PM2.5-induced oxidative stress: (A) malondialdehyde (MDA) concentration in serum, (B) MDA concentration in the heart, (C) superoxide dismutase (SOD) activity in serum, and (D) SOD activity in the heart. All data represent the mean ± SEM; #p < 0.05 compared to the control group, *p < 0.05 compared to the PM2.5 exposure group.

Oxidants and Antioxidants. The increase in MDA concentration was considerable in the PM2.5-exposed group in both serum and heart. However, rats treated with 1.0 g/kg BAE showed a decrease in MDA concentration, again in both serum and heart (Figure 6A,B). Serum SOD activity was similar in the BAE treatment groups and PM2.5-exposure group (Figure 6C). However, SOD activity in the heart tissue of rats exposed to PM2.5 significantly decreased in comparison with the control group. In addition, SOD activity in the heart tissue was significantly higher in the rats treated with 1.0 g/kg BAE, when compared with the PM2.5 exposure group (Figure 6D). Bax and Bcl-2 Protein Expression in Heart Tissue. To investigate the effects of BAE on PM2.5-induced cardiomyocyte apoptosis, we measured the expression of the apoptosis-related proteins Bax and Bcl-2. PM2.5 exposure increased Bax expression and decreased Bcl-2 expression. However, 1.0 g/kg BAE significantly reduced the expression of Bax and Bcl-2 in cardiomyocytes (Figure 7, 1−3). Histopathological Evaluation. The examination of cardiac tissues and aorta showed no detectable inflammation or injury in any experimental group (Figure 8).

PM2.5 + BAE (2.0 g/kg) group was also abnormal, and similar to that of rats in the PM2.5 group (Figure 2E). Myocardial Enzyme Levels. There were no differences among the treatment groups in serum LDH levels (Figure 3A) or LDH content in heart tissue (Figure 3B). PM2.5 exposure significantly increased serum CK, whereas treatment with 1.0 g/kg BAE markedly reduced serum CK concentrations (Figure 3C). There was no statistical difference in CK activity in heart tissue between groups (Figure 3D). PM2.5 exposure significantly increased CK-MB activity in serum and heart tissue, whereas treatment with 1.0 g/kg BAE markedly reduced CK-MB activity. However, CK-MB activity in the heart tissue of the PM2.5 + BAE (2.0 g/kg) group increased significantly compared with that in the PM2.5 + BAE (1.0 g/kg) group (Figures 3E,F). Endothelial System Functional Changes. ET-1 and angiotensin II increased significantly in the rats exposed to PM2.5 in comparison with the control group. In contrast, 1.0 and 2.0 g/kg BAE significantly reduced ET-1 and angiotensin II concentrations (Figures 4A,B). Systemic Inflammation and Injury. Exposure to PM2.5 three times was sufficient to significantly increase IL-6 levels. Interestingly, the group that received 1.0 g/kg BAE demonstrated a decrease in IL-6 levels compared with the levels in the PM2.5-exposed group (Figure 5A). In contrast, IL-10 levels decreased significantly in the group exposed to PM2.5 in comparison with the control group and markedly increased in the PM2.5 + BAE (1.0 g/kg) group compared with the PM2.5-exposed group (Figure 5B). PM2.5 exposure induced a significant increase in CRP, which decreased significantly in the 1.0 g/kg BAE treatment group (Figure 5C).

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DISCUSSION Many studies showed that particulate matter (PM2.5) is closely associated with cardiovascular disease (CVD). Farraj et al. found that concentrated ambient particulate exposure resulted in a greater decrease in rat HR than filtered air exposure in winter time.19 This decrease in HR was reported in another study, which aimed to identify the mechanisms of cardiovascular E

DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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and CK-MB increased significantly in the PM2.5-exposed group compared to the control group. However, there were no differences in serum LDH levels among the treatment groups. We found that PM2.5 induced cardiac dysfunction. In addition, because of the tolerance capacity of healthy myocardial tissue, a small degree of cardiac injury may not be apparent.22−24 This may explain why no abnormalities were detected in the heart and aorta after PM2.5 exposure in our study. Similar results were reported in a study estimating the effects of vanadium-rich respirable oil combustion PM (HP-10) on intrinsic myocardial ischemic tolerance and mitochondrial integrity in rats.25 BAE administration improved abnormal ECG types and reduced biomarkers of cardiac injury. These findings support the conclusion that BAE attenuated PM2.5-induced cardiac dysfunction. In the present study, we found that there were no significant differences between the PM2.5 + BAE (2.0 g/kg) group and the PM2.5-exposed group. It has been reported that procyanidins and grape extracts containing high concentrations of procyanidins exerted negative effects on health because highly antioxidant products can also be cytotoxic.26−28 High doses of cyanidin-3-O-β-glucopyranoside induced apoptosis in transformed and normal T cells, owing to an increase in p53 and Bax protein expression.29 However, the mechanism of action underlying these effects is not yet known; therefore, complementary studies are needed to clarify the potential mechanisms of action of BAE. In addition, BAE attenuated PM2.5-induced inflammatory cytokine expression and ameliorated oxidative stress, endothelial dysfunction, and cardiomyocyte apoptosis. Inflammation and oxidative stress are considered to be closely related to CVD. In this study, we found that PM2.5 exposure changed the expression of several cytokines, such as CRP, IL-6, and the antiinflammatory IL-10. These effects were ameliorated by BAE. It has also been reported that anthocyanins can inhibit CRP and IL-6 expression and promote IL-10 secretion.30−32 The present study found that BAE attenuated a PM2.5-induced increase in MDA levels and a decrease in SOD activity, exhibiting antioxidant properties, consistent with finding from other studies.12,33 The endothelial system plays a major role in cardiovascular physiology. ET-1, synthesized by cardiomyocytes, fibroblasts, and endothelial cells, directly stimulates cardiac fibroblasts to produce extracellular matrix proteins, thus promoting myocardial fibrosis, and is considered a prognostic indicator of cardiac

Figure 7. Blueberry anthocyanin-enriched extracts (BAE) attenuated PM2.5-induced cardiomyocyte apoptosis. (1) Western blot: (A) control group, (B) PM2.5 exposure group, (C) PM2.5 + BAE (0.5 g/kg) group, (D) PM2.5 + BAE (1.0 g/kg) group, and (E) PM2.5 + BAE (2.0 g/kg) group. (2) Relative Bax levels in the heart. (3) Relative Bcl-2 levels in the heart. All data represent the mean ± SEM; #p < 0.05 compared to the control group, *p < 0.05 compared to the PM2.5 exposure group.

toxicity induced by ambient PM2.5 and ozone.20 We found that HR decreased significantly in response to PM2.5. On the other hand, we also found that instillation of PM2.5 induced ST segment depression or elevation in rats, which is related to ischemic heart disease. Increased activity of cardiac enzymes, including CK, CK-MB, and LDH, is a well-known diagnostic indicator of cardiac injury, which is associated with myocardial infarction, myocarditis, and heart failure.20,21 In this study, CK

Figure 8. Morphological characteristics of the heart and aorta of rats. (A−E) Histopathological analysis of the heart: (A) control group, (B) PM2.5 exposure group, (C) PM2.5 + BAE (0.5 g/kg) group, (D) PM2.5 + BAE (1.0 g/kg) group, and (E) PM2.5 + BAE (2.0 g/kg) group. (F−J) Histopathological analysis of the aorta: (F) control group, (G) PM2.5 exposure group, (H) PM2.5 + BAE (0.5 g/kg) group, (I) PM2.5 + BAE (1.0 g/kg) group, and (J) PM2.5 + BAE (2.0 g/kg) group. F

DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry mortality.34,35 Angiotensin II, the final active messenger of the renin−angiotensin system (RAS), is associated with vasoconstriction, stimulation of myocytes, and facilitation of norepinephrine release from sympathetic neurons.36 Angiotensin-II converting enzyme (ACE) catalyzes the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II. In contrast, BAE can inhibit ACE activity, resulting in blood pressure reduction in stroke-prone SHR.37 Our results show that BAE can attenuate PM2.5-induced up-regulation of ET-1 and angiotensin II. Bax is a pro-apoptotic protein of the Bcl-2 family and is capable of directly triggering apoptosis. Conversely, Bcl-2 is a critical antiapoptotic protein, which is activated in response to oxidative stress.21 Anthocyanins have been found to inhibit apoptosis by reducing cytosolic cytochrome c and promoting cytochrome c-induced mitochondrial respiration,16 probably by prevention of calpain activation and oxidative stress.38 In the present study, PM2.5 exposure resulted in a significant increase in Bax protein expression and a significant decrease in Bcl-2 protein expression in cardiac tissues. However, BAE attenuated these PM2.5-induced changes. In summary, the data suggest that PM2.5-induced cardiovascular dysfunction, including mean HR decrease, cardiac enzyme activity increase, and abnormal ECG types, may be attributed to inflammatory responses, oxidative stress, endothelial dysfunction, and cardiomyocyte apoptosis. Moreover, BAE at certain doses may inhibit PM2.5-induced cardiovascular dysfunction by anti-inflammatory and antioxidant properties, exerting positive effects on endothelial function and inhibiting apoptosis.

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(3) Mustafic, H.; Jabre, P.; Caussin, C.; Murad, M. H.; Escolano, S.; Tafflet, M.; Perier, M. C.; Marijon, E.; Vernerey, D.; Empana, J. P.; Jouven, X. Main air pollutants and myocardial infarction: a systematic review and meta-analysis. JAMA 2012, 307, 713−721. (4) Xie, W.; Li, G.; Zhao, D.; Xie, X.; Wei, Z.; Wang, W.; Wang, M.; Li, G.; Liu, W.; Sun, J.; Jia, Z.; Zhang, Q.; Liu, J. Relationship between fine particulate air pollution and ischaemic heart disease morbidity and mortality. Heart 2015, 101, 257−263. (5) Franchini, M.; Mannucci, P. M. Thrombogenicity and cardiovascular effects of ambient air pollution. Blood 2011, 118, 2405−2412. (6) van Eeden, S. F.; Yeung, A.; Quinlam, K.; Hogg, J. C. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2005, 2, 61−67. (7) Lodovici, M.; Bigagli, E. Oxidative stress and air pollution exposure. J. Toxicol. 2011, 2011, 1−9. (8) Rui, W.; Guan, L.; Zhang, F.; Zhang, W.; Ding, W. PM2.5induced oxidative stress increases adhesion molecules expression in human endothelial cells through the ERK/AKT/NF-kappaB-dependent pathway. J. Appl. Toxicol. 2016, 36, 48−59. (9) Mossman, B. T. Introduction to serial reviews on the role of reactive oxygen and nitrogen species (ROS/RNS) in lung injury and diseases. Free Radical Biol. Med. 2003, 34, 1115−1116. (10) Bo, L.; Jiang, S.; Xie, Y.; Kan, H.; Song, W.; Zhao, J. Effect of vitamin E and omega-3 fatty acids on protecting ambient PM2.5induced inflammatory response and oxidative stress in vascular endothelial cells. PLoS One 2016, 11, e0152216. (11) Liu, Y.; Tan, D.; Shi, L.; Liu, X.; Zhang, Y.; Tong, C.; Song, D.; Hou, M. Blueberry anthocyanins-enriched extracts attenuate cyclophosphamide-induced cardiac injury. PLoS One 2015, 10, e0127813. (12) Coban, J.; Evran, B.; Ozkan, F.; Cevik, A.; Dogru-Abbasoglu, S.; Uysal, M. Effect of blueberry feeding on lipids and oxidative stress in the serum, liver and aorta of guinea pigs fed on a high-cholesterol diet. Biosci., Biotechnol., Biochem. 2013, 77, 389−391. (13) Zhu, Y.; Xia, M.; Yang, Y.; Liu, F.; Li, Z.; Hao, Y.; Mi, M.; Jin, T.; Ling, W. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin. Chem. 2011, 57, 1524−1533. (14) Kristo, A. S.; Kalea, A. Z.; Schuschke, D. A.; Klimis-Zacas, D. Attenuation of alpha-adrenergic-induced vasoconstriction by dietary wild blueberries (Vaccinium angustifolium) is mediated by the NOcGMP pathway in spontaneously hypertensive rats (SHRs). Int. J. Food Sci. Nutr. 2013, 64, 979−987. (15) Kristo, A. S.; Malavaki, C. J.; Lamari, F. N.; Karamanos, N. K.; Klimis-Zacas, D. Wild blueberry (V. angustifolium)-enriched diets alter aortic glycosaminoglycan profile in the spontaneously hypertensive rat. J. Nutr. Biochem. 2012, 23, 961−965. (16) Skemiene, K.; Rakauskaite, G.; Trumbeckaite, S.; Liobikas, J.; Brown, G. C.; Borutaite, V. Anthocyanins block ischemia-induced apoptosis in the perfused heart and support mitochondrial respiration potentially by reducing cytosolic cytochrome c. Int. J. Biochem. Cell Biol. 2013, 45, 23−29. (17) Johnson, M. H.; de Mejia, E. G. Phenolic Compounds from Fermented Berry Beverages Modulated Gene and Protein Expression To Increase Insulin Secretion from Pancreatic β-Cells in Vitro. J. Agric. Food Chem. 2016, 64, 2569−2581. (18) Yang, H.; Pang, W.; Lu, H.; Cheng, D.; Yan, X.; Cheng, Y.; Jiang, Y. Comparison of metabolic profiling of cyanidin-3-Ogalactoside and extracts from blueberry in aged mice. J. Agric. Food Chem. 2011, 59, 2069−2076. (19) Farraj, A. K.; Walsh, L.; Haykal-Coates, N.; Malik, F.; McGee, J.; Winsett, D.; Duvall, R.; Kovalcik, K.; Cascio, W. E.; Higuchi, M.; Hazari, M. S. Cardiac effects of seasonal ambient particulate matter and ozone co-exposure in rats. Part. Fibre Toxicol. 2015, 12, 12. (20) Wang, G.; Zhen, L.; Lu, P.; Jiang, R.; Song, W. Effects of ozone and fine particulate matter (PM2.5) on rat cardiac autonomic nervous system and systemic inflammation. Wei Sheng Yan Jiu 2013, 42, 554− 560.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.6b04603. Content of BAE (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*Yugang Jiang. E-mail: [email protected]. Tel: +86 02284655333. *Changjiang Guo. E-mail: [email protected]. Tel: +86 02284655429. ORCID

Ziyu Wang: 0000-0002-7841-0072 Funding

The study was supported by the 2014 Chinese Nutrition Society (CNS) Nutrition Research Foundation’s DSM Research Fund (No. 2014−032). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank all colleagues and students who contributed to this study. REFERENCES

(1) Anakwue, R. C.; Anakwue, A. C. Cardiovascular disease risk profiling in Africa: Environmental pollutants are not on the agenda. Cardiovasc. Toxicol. 2014, 14, 193−207. (2) Martinelli, N.; Olivieri, O.; Girelli, D. Air particulate matter and cardiovascular disease: a narrative review. Eur. J. Intern. Med. 2013, 24, 295−302. G

DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.jafc.6b04603 J. Agric. Food Chem. XXXX, XXX, XXX−XXX