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Logo of oximedOxidative Medicine and Cellular Longevity
Oxid Med Cell Longev. 2013; 2013: 901239.
Published online 2013 April 22. doi:  10.1155/2013/901239
PMCID: PMC3655674

The Influence of Nrf2 on Cardiac Responses to Environmental Stressors


Nrf2 protects the lung from adverse responses to oxidants, including 100% oxygen (hyperoxia) and airborne pollutants like particulate matter (PM) exposure, but the role of Nrf2 on heart rate (HR) and heart rate variability (HRV) responses is not known. We hypothesized that genetic disruption of Nrf2 would exacerbate murine HR and HRV responses to severe hyperoxia or moderate PM exposures. Nrf2−/− and Nrf2+/+ mice were instrumented for continuous ECG recording to calculate HR and HRV (low frequency (LF), high frequency (HF), and total power (TP)). Mice were then either exposed to hyperoxia for up to 72 hrs or aspirated with ultrafine PM (UF-PM). Compared to respective controls, UF-PM induced significantly greater effects on HR (P < 0.001) and HF HRV (P < 0.001) in Nrf2−/− mice compared to Nrf2+/+ mice. Nrf2−/− mice tolerated hyperoxia significantly less than Nrf2+/+ mice (~22 hrs; P < 0.001). Reductions in HR, LF, HF, and TP HRV were also significantly greater in Nrf2−/− compared to Nrf2+/+ mice (P < 0.01). Results demonstrate that Nrf2 deletion increases susceptibility to change in HR and HRV responses to environmental stressors and suggest potential therapeutic strategies to prevent cardiovascular alterations.

1. Introduction

The deleterious effects of environmental exposures and associated oxidative stress on the cardiopulmonary system are well established and present one of the most significant public health problems [1]. Diseases and disorders of the cardiopulmonary system associated with an enhanced oxidant load include, but are not limited to, inflammatory lung diseases (e.g., acute respiratory distress syndrome [2] and bronchopulmonary dysplasia [3, 4]) and a host of cardiovascular (CV) diseases (e.g., atherosclerosis [5, 6], hypertension [7], and heart failure [8]).

Exposure to oxidants can exacerbate the pathogenesis of these diseases by further increasing oxidative stress and in some cases overwhelm antioxidant defenses. Inflammatory lung disease and post-resuscitation from cardiac arrest are frequently treated with oxygen therapy (hyperoxia), which can cause significant lung injury [9], adverse cardiac responses [10], and death if exposure is sufficiently long, even in young healthy laboratory animals.

However, not all oxidants such as air pollution produce overt outcomes, but they are no less problematic in terms of public health because exposure is frequent, wide spread, and exacerbated by other influential factors such as age and preexisting disease. One prominent example is exposure to particulate matter (PM). PM is a diverse composition of metals and inorganic matter, the constituents of which are dependent on the source, geographic region, and particle aerodynamic diameter which have been reviewed in detail [11]. Exposure to PM is known to induce pulmonary [1214] and cardiovascular [15, 16] responses, which have been associated with increases in hospital admissions and premature mortality (for review [17]), especially in those with preexisting cardiopulmonary disease. Direct and indirect pathways for PM-induced effects on cardiovascular function have been proposed ([18, 19] for review). Indirect effects include lung exposure derived influences on the cardiovascular system via alterations in nervous system function [20, 21], thus altering heart rate variability (HRV) [2224] and systemic [25] and/or vascular inflammation [26]. Direct PM effects on cardiovascular function have been associated with infiltration of PM, especially PM with an aerodynamic diameter of <0.1 μm (UF-PM) [27, 28]. Subsequent effects include vascular dysfunction [29, 30] and increased oxidant burden [3133].

Resistance to oxidant stress relies upon effective antioxidant defenses including enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1), superoxide dismutase (SOD), glutathione peroxidases, and heme oxygenase-1 (HO-1). These and other phase II enzyme genes contain promoter antioxidant response elements (AREs) which bind to a heterodimer containing a small Maf protein and nuclear factor-erythroid 2-(NF-E2-) related factor 2-(Nrf2), a member of the Cap “n” Collar family of transcription factors. Although the role of Nrf2 in cardiovascular diseases is complex (refer to a review by R. Howden in the current issue), it has been implicated in resistance against lung injury induced by oxidant exposure [3436].

Recently, significant adverse changes in cardiac function were reported in mice during exposure to hyperoxia [10], a well-established murine model for acute lung injury and inflammatory lung disease [37, 38], and results suggested a genetic component to cardiac responses. Furthermore, several studies have reported cardiovascular responses to PM exposure, especially heart rate variability (HRV), but genetic factors leading to susceptibility are poorly defined (for review [39]).

Changes in HR and HRV are accepted as indicators for increases in cardiovascular risk, including in response to oxidative stress [10, 4042]. The purpose of this study was to test the hypothesis that Nrf2 protects against the cardiac responses (HR and HRV) to hyperoxia or UF-PM exposure and improve understanding of the widespread importance of Nrf2 activity in resistance to oxidative stress.

2. Materials and Methods

2.1. Animals and Survival Surgery

Male ICR/sv129: Nrf2−/− and ICR/sv129: Nrf2+/+ (wild-type littermates) mice were obtained from a colony maintained at NIEHS, and were originally developed at Tsukuba University [43]. Mice n = 8 − 16 (per strain; 20–30 g; 8–12 weeks of age) were housed individually in standard polycarbonate cages with a 12 : 12 hours light-dark cycle. Food (AIN-76A) and water were provided ad libitum. Animals were handled in accordance with The National Institutes of Health Humane Care and Use of Laboratory Animals guidelines. The study protocol was reviewed and approved by the National Institute of Environmental Health Science Animal Care and Use Committee.

Mice were anesthetized with inhaled isoflurane (1.5–2% in oxygen) with buprenorphine (0.1 mg/Kg) given for analgesia. Following a midline dorsal cutaneous incision (3 cm), a subcutaneous tissue pocket was made with a blunt instrument, into which an ETA-F20 ECG transmitter (DSI; Arden Hills, MN, USA) was placed. The positive and negative ECG leads were sutured over the left superficial gluteus and right trapezius muscles, respectively. All incisions were closed using wound clips and animals recovered for five days.

2.2. Hyperoxia and Ultrafine Particulate Matter (UF-PM) Exposure

Prior to any exposure, mice were housed in individual whole body plethysmographs (Buxco Electronics, Wilmington, NC, USA) and allowed at least 30 minutes to become quiescent before recording 20 minutes of baseline ECG. Mice of each genotype were randomly assigned to the following groups: group 1, UF-PM exposure by aspiration (n = 4 per strain; normoxia); group 2, saline exposure by aspiration under normoxic conditions (n = 4 per strain; normoxia); and group 3, hyperoxia exposure (n = 8 per strain; no UF-PM or saline exposure). The number of mice exposed to UF-PM (group 1) was lower because the particles were in limited supply.

UF-PM (aerodynamic diameter <0.1 μm) was collected at the University of North Carolina at Chapel Hill in 2002 [44]. Mice were anesthetized by isoflurane and exposed by aspiration to 100 μg UF-PM suspended in 50 μL of sterile 0.9% saline (group 1) or 50 μL of sterile 0.9% saline only (group 2). Saline/UF-PM suspension was vortexed immediately prior to dosing each animal. Within 10–15 min of UF-PM exposure, mice were housed in whole body plethysmographs (for consistency with hyperoxia exposure procedures below) for 48 hr of continuous ECG data recording.

Group 3 mice were exposed to 100% oxygen using individual whole body plethysmographs as exposure chambers. The oxygen was delivered from a liquid oxygen tank, warmed to room temperature, and sufficiently humidified. ECG was recorded continuously, while mice were exposed to hyperoxia for a maximum of 72 hr, until moribund or when HR declined to ~250 bpm. These endpoints were chosen based on previous studies of prolonged hyperoxia exposure of inbred mice [10].

R-R interval and HR data were calculated from the ECG records using specialist ECG pattern recognition software (Ponemah, v4.8-SP4). We calculated HRV using a Lomb periodogram as described previously [45]. The frequency ranges used were 0.2–1.5 Hz (low frequency; LF) and 1.5–50 Hz (high frequency; HF), and a summation of the LF and HF was used to represent total power (TP).

2.3. Statistical Analysis

Group mean baseline phenotypic values (HR and HRV) for each genotype were calculated, and differences were assessed independently using a one-way ANOVA (alpha level was set at 0.05). HR and HRV responses (hourly means ± SEM) to hyperoxia (genotype X time) were assessed independently using a two-way ANOVA with SNK post hoc test for pairwise comparisons up to the common length of exposure time between Nrf2−/− and Nrf2+/+ groups (45 hr exposure; alpha level was set at 0.05). Differences in HR and HRV phenotypes between baseline and hyperoxia (hourly means ± SEM) were assessed for each genotype using a one-way ANOVA (alpha level was set at 0.05). To assess changes in HR and HRV in response to hyperoxia in the Nrf2+/+ mice (i.e., a longer exposure time compared to Nrf2−/−) from baseline, a one-way ANOVA (P < 0.05) was used. HR and HRV responses to UF-PM exposure (genotype X treatment X time) were assessed independently using a three-way ANOVA with Students-Newman-Keuls post hoc test for pairwise comparisons (alpha level was set at 0.05).

3. Results

3.1. HR and HRV Responses to UF-PM

No significant differences in group mean baseline HR, LF, HF, or TP were detected between Nrf2−/− and Nrf2+/+ (519.8 ± 18.3 versus 482.8 ± 13.9 bpm; 1.14 ± 0.17 versus 1.51 ± 0.16 ms2/Hz; 0.94 ± 0.17 versus 0.75 ± 0.09 ms2/Hz; and 2.08 ± 0.18 versus 2.26 ± 0.22 ms2/Hz, resp.; Figures 1(a)1(d)). However, compared to saline, a significant overall increased effect of UF-PM exposure on HR responses was found in Nrf2−/− mice (48 hr mean difference 21.26 bpm; P < 0.001; Figure 1(a) and Table 1) but not in Nrf2+/+ mice. Moreover, HR responses were significantly greater in Nrf2−/− compared to Nrf2+/+ mice treated with UF-PM (48 hr mean difference 24.26 bpm; P < 0.001).

Figure 1
(a) Heart rate (HR, bpm) responses in Nrf2−/− and Nrf2+/+ mice following aspiration of either ultrafine particulate matter (UF-PM, <0.1 μm) in saline or saline alone. Significant overall effects between treatment ...
Table 1
Pairwise comparisons for overall effects between three-way ANOVA factors for heart rate (HR) and heart rate variability (HRV) responses to ultrafine particulate matter (UF-PM) or saline control.

A significant overall reduction effect of UF-PM treatment on LF HRV responses (48 hr mean difference 0.02 ms2/Hz; P = 0.048; Figure 1(b) and Table 1) was also found, but it was not dependent on genotype. However, multiple significant effects on HF HRV were detected (Figure 1(c) and Table 1). Interestingly, an overall significantly increased HF HRV was found within Nrf2−/− mice treated with UF-PM versus saline (48 hr mean difference 0.37 ms2/Hz; P < 0.001), but not within Nrf2+/+ mice (Table 1). Moreover, overall genotype effects were found for saline and UF-PM treatment groups (48 hr mean difference 0.15 ms2/Hz; P = 0.019 and 48 hr mean difference 0.33 ms2/Hz; P < 0.001, resp.; Table 1). However, it is important to note that the studentized range distribution (q value) was more than three times higher when comparing Nrf2+/+ and Nrf2−/− treatment groups (q = 2.40 and 9.04, resp.) and more than twice as high for Nrf2+/+ versus Nrf2−/− within UF-PM or saline (q = 3.32 and 8.06 resp.; Table 1), suggesting a greater effect in Nrf2−/− mice when treated with UF-PM. Moreover, the interactions for HF HRV between genotypes within each treatment group were opposing. Overall, HF HRV was higher in Nrf2+/+ versus Nrf2−/− mice following saline treatment, but HF HRV was higher in Nrf2−/− versus Nrf2+/+ mice following UF-PM treatment (Table 1). Specific time points at which these differences occurred were undetectable, perhaps due to the high degree of variability in the Nrf2−/− UF-PM treated group.

TP HRV is the sum of HF and LF HRV, and multiple overall effects were found (Figure 1(d) and Table 1), but specific time points at which these differences occurred were not detectable. Overall differences in TP HRV responses between UF-PM and saline treatment were found within Nrf2+/+ and Nrf2−/− groups (48 hr mean difference for Nrf2+/+, 0.17 ms2/Hz, P = 0.007; 48 hr mean difference for Nrf2−/−, 0.35 ms2/Hz, P < 0.001). Moreover, Nrf2−/− and Nrf2+/+ groups were different from each other with respect to TP HRV responses irrespective of treatment (48 hr mean difference after saline, 0.19 ms2/Hz, P = 0.004; 48 hr mean difference after UF-PM, 0.34 ms2/Hz, P < 0.001). However, the q value was approximately twice as high when comparing Nrf2+/+ and Nrf2−/− treatment groups (q = 3.78 and 8.22, resp.) and Nrf2+/+ and Nrf2−/− within UF-PM or saline (q = 4.06 and 7.93, resp.), again suggesting a greater effect in Nrf2−/− mice treated with UF-PM, although this effect was primarily influenced by HF HRV responses as the interactions were similar (Table 1). Despite the significant differences in HR and HRV responses between treatment and genotype, we were not able to detect specific posttreatment time points where these differences lie.

3.2. HR and HRV Responses to Hyperoxia

In mice used for hyperoxia exposures, no significant differences in group mean (±SEM) baseline HR, LF, HF, or TP were detected between Nrf2−/− and Nrf2+/+ (484.2 ± 21.2 versus 486.6 ± 12.3 bpm; 1.17 ± 0.18 versus 1.35 ± 0.10 ms2/Hz; 1.25 ± 0.18 versus 1.12 ± 0.14 ms2/Hz; 2.42 ± 0.17 versus 2.47 ± 0.17 ms2/Hz, resp.; Figure 2).

Figure 2
Time to heart rates of 250 bpm in Nrf2−/− and Nrf2+/+ mice during hyperoxia (100% oxygen) exposure. *Significantly different between genotypes (P < 0.001). Group means ± SEM are presented (n = 8/group).

Group mean (±SEM) HR of Nrf2−/− mice reduced to below 250 bpm in significantly less time compared to Nrf2+/+ mice (determined by the first hr at which individual mouse HR was less than 250 bpm was detected; 41.6 ± 1.9 versus 64.0 ± 2.9 hours; P < 0.001; Figure 2). Prolonged hyperoxia caused highly significant and precipitous reductions in HR after a period of normal circadian variation, which was genotype dependent. Compared to respective genotype mean baseline values, HR reduced significantly in Nrf2−/− mice after 34 hrs hyperoxia (group mean difference 178.2 bpm; P < 0.001) and continued to decline until exposure terminated at 45 hrs (group mean difference 234.4 bpm; P < 0.001; Figure 3(a)). In Nrf2+/+ mice, the decline in HR compared to baseline was not significant until 54 hrs hyperoxia (group mean difference 147.8 bpm; P < 0.001; Figure 3) and 20 hrs after a significant group mean HR reduction in Nrf2−/− mice. HR continued to decline in Nrf2+/+ mice until exposure terminated at 70 hr (group mean difference 236.4 bpm; P < 0.001; Figure 3(a)).

Figure 3
(a) Hourly mean heart rate (HR, bpm) responses in Nrf2−/− and Nrf2+/+ mice during hyperoxia (100% oxygen) exposure. Heart rates in Nrf2−/− mice were significantly reduced from baseline from 34 hr until the end of ...

LF HRV was significantly reduced in Nrf2−/− mice compared to Nrf2+/+ mice after 40 hrs hyperoxia (group mean difference 0.63 ms2/Hz; P = 0.01; Figure 3(b)) and continued to decline until the Nrf2−/− mice were euthanized. No significant changes in LF HRV were detected in the Nrf2+/+ mice during hyperoxia. Within each genotype, no significant effect of hyperoxia on HF HRV was found, except after 35 and 36 hrs of hyperoxia when HF HRV was significantly reduced in Nrf2−/− mice compared to Nrf2+/+ mice (group mean difference 0.71 ms2/Hz; P < 0.001 and group mean difference 0.81 ms2/Hz; P < 0.001; Figure 3(c)). Thereafter, no differences in mean HF HRV were found between genotypes. Because TP HRV is the sum of LF and HF HRV, it was not surprising to find a significant overall genotype effect during hyperoxia exposure (group mean difference 0.24 ms2/Hz; P < 0.001; Figure 3(d)). Mean TP HRV in Nrf2−/− mice was significantly lower compared to Nrf2+/+ mice from 43 hr exposure (group mean difference 0.92 ms2/Hz; P = 0.03) to the end of exposure in Nrf2−/− mice (45 hrs).

4. Discussion

Factors contributing to oxidative stress are widely accepted as important to the pathogenesis of cardiopulmonary diseases. Examples include inflammatory lung diseases, exposure to oxidant air pollution, and a wide range of clinical scenarios that require oxygen therapy with high fraction of inspired oxygen (FiO2; for example, acute respiratory distress syndrome and postmyocardial infarction patients). Understanding susceptibility mechanisms for severe oxidant stresses (such as advanced cardiopulmonary disease or high FiO2) or less severe changes in oxidant burden (such as air pollution exposure) is a primary public health concern. Importantly, overlap in responsible mechanisms between oxidative stress inducing exposures could partially explain reported extremes in susceptibility or resistance to adverse reactions. A prominent example is the negative effect of preexisting cardiopulmonary disease on susceptibility to adverse cardiac responses to oxidative stress and poor responses to further oxidant burden induced by oxygen therapy, all of which may operate through the same or similar mechanisms.

In this study, we found that Nrf2 was important in cardiac responses to a severe (hyperoxia) and moderate (UF-PM) oxidant stress. A central role for Nrf2 in resistance to hyperoxia-induced lung injury has been described in detail [34, 35], and Nrf2 appears to be also important in epithelial cell response to particle exposure [46], especially when combined with allergy and/or asthma [36]. Since interactions between the cardiovascular and pulmonary systems are well known, lung injury response to oxidative stress is likely to involve the heart. Moreover, an influence of oxidative stress on cardiac function has been demonstrated, especially during hypoxia [47], reperfusion injury [48], and in response to particle exposure [49]. Because Nrf2 is established as critically important in antioxidant defense, this suggests that oxidative stress was a common component to hyperoxia and UF-PM cardiac responses in this study.

HR responses to UF-PM exposure were statistically significant though not as severe as responses to hyperoxia (see Figures Figures11 and and3).3). Nonetheless, the changes elicited by UF-PM may have physiological relevance because the mice used were young and healthy and were otherwise not compromised. Targeted deletion of Nrf2 exacerbated the HR responses, though the mechanism through which Nrf2 protects against the response remains unclear. It would also be of interest to determine whether interactions exist between Nrf2 and preexisting disease and/or age, both of which are important susceptibility factors associated with PM exposure [5054].

Cardiovascular responses to particulate matter exposures have been investigated in detail ([55] for review). However, little is known about genetic susceptibility to particle exposure or which sectors of the population are most at risk. Because such a large percentage of the global population is exposed to particulate matter, this presents the potential for widespread adverse health outcomes and highlights the importance of understanding susceptibility. In this study, we found overall effects of Nrf2 deletion on cardiac responses to UF-PM that could act through similar mechanisms that become important in a compromised host, especially since pre-existing disease is an important factor in susceptibility to UF-PM exposure [52, 54, 56]. These effects may not have manifested in this experiment since all mice were otherwise healthy, and therefore subtle responses were produced.

Previously, we reported highly significant HR responses to hyperoxia that preceded changes in pulmonary function and lung injury [10], suggesting that cardiac responses to oxidative stress may predict impending adverse pulmonary events. In the present study, we found similar HR responses to hyperoxia, and Nrf2−/− mice were highly susceptible compared to Nrf2+/+ mice, reaching the HR end point of 250 bpm ~22 hr before Nrf2+/+ mice (Figure 2). Hyperoxia is known to cause significant lung injury, pulmonary edema and, at least in patients with acute respiratory distress syndrome, for which hyperoxia is a model, poor gas exchange leading to hypoxemia [5759]. Although we were unable to measure blood gases during hyperoxia exposure, it is known that bradycardia can result from either hypoxemia and/or permissive hypercapnia, as a consequence of respiratory insufficiency [6062], which may be associated with chemoreceptor activation and respiratory acidosis [60]. These mechanisms may be partially responsible for the severe bradycardia observed in this and previous studies [10] exposing mice to prolonged hyperoxia, which warrants further investigation. Decreases in HF HRV have been observed when mice were exposed to a hypoxia/hypercapnia combination, suggesting a role for autonomic nervous system (ANS) control of the heart under these conditions. In this study, we found opposing overall genotype effects (Nrf2−/− versus Nrf2+/+) for HRV phenotypes during hyperoxia or after UF-PM exposure (decreases during hyperoxia and increases following UF-PM). While these data suggest an interaction between Nrf2 and ANS function, the opposing effects of hyperoxia and UF-PM treatment on HRV are challenging to interpret because the correlation between changes in HRV and ANS tone is currently a matter of debate (for review [63]). Nonetheless, our data do suggest a disturbance in autonomic regulation of cardiac function during hyperoxia and after UF-PM treatment that was modulated by Nrf2. These HRV changes may therefore have important implications for susceptibility to adverse cardiac outcomes in response to oxidant exposure.

However, since hypoxia and hypercapnia are unlikely to result from UF-PM exposure, Nrf2 may act through different mechanisms compared to hyperoxia exposure. For example, Nrf2 has been implicated in defense against cadmium-induced oxidative stress in the olfactory bulb of zebrafish [64]. Interestingly, human olfactory bulb stimulation is associated with changes in HRV [65], and UF particles have been shown to translocate from the lung to the olfactory bulb of rats [66]. Taken together, it is possible that changes in HR and HRV following UF-PM exposure in this study were partially mediated through UF-PM-induced oxidative stress effects on the olfactory bulb.

While speculative, a contributory mechanism for the observed HR and HRV responses to hyperoxia could be associated with the candidate gene thrombospondin, type 1, domain containing 4 (ThSD4 or AdAMTSL6) [10]. Adamtsl6 has been reported to bind directly to fibrillin-1 (Fbn-1), initiating widespread extracellular matrix (ECM) assembly, including the myocardium [67]. Fbn-1 mediates bone morphogenetic protein-induced expression of important ECM collagens. Interestingly, absence of Fbn-1 is associated with Marfan's syndrome [68], and over expression leads to myocardial fibrosis [69]. Moreover, changes in the myocardial ECM is associated with the development of diastolic dysfunction in heart failure, even in the short term, possibly through the renin-angiotensin-aldosterone system ([70] for review). Regulation of these genes have been linked to Nrf2 expression levels during hyperoxia exposure in mice [71], which may explain part of the cardiac responses observed here during hyperoxia or following UF-PM exposures. Further work is required to determine the importance of changes in ECM proteins in cardiac responses to oxidative stress.

5. Conclusions

In this study, we found that severe (hyperoxia) and moderate (UF-PM) environmental oxidant stressors caused HR and HRV responses in the mouse, and targeted deletion of Nrf2 significantly augmented the detrimental responses to these environmental oxidants. The magnitude of cardiac functional responses may have been proportional to the degree of oxidant burden during hyperoxia or after UF-PM aspiration. Understanding the mechanisms by which the myocardium defends against these stressors is critical for identifying individuals at risk, and we provide evidence that Nrf2 may be an important determinant in defense against severe and moderate oxidative stress.

Conflict of Interests

The authors confirm that no conflict of interests exists in relation to this paper.


This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services. The contents of this publication do not necessarily reflect the views and policies of the US Environmental Protection Agency.


1. Block G, Dietrich M, Norkus EP, et al. Factors associated with oxidative stress in human populations. American Journal of Epidemiology. 2002;156(3):274–285. [PubMed]
2. Lang JD, McArdle PJ, O’Reilly PJ, Matalon S. Oxidant-antioxidant balance in acute lung injury. Chest. 2002;122(6, supplement):314S–320S. [PubMed]
3. Saugstad OD. Bronchopulmonary dysplasia—oxidative stress and antioxidants. Seminars in Neonatology. 2003;8(1):39–49. [PubMed]
4. Saugstad OD. Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD? Acta Paediatrica, International Journal of Paediatrics. 1997;86(12):1277–1282. [PubMed]
5. Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H. Role of oxidative stress in atherosclerosis. American Journal of Cardiology. 2003;91(3, supplement):7–11. [PubMed]
6. Park JG, Oh GT. The role of peroxidases in the pathogenesis of atherosclerosis. BMB Reports. 2011;44(8):497–505. [PubMed]
7. Harrison DG, Gongora MC, Guzik TJ, Widder J. Oxidative stress and hypertension. Journal of the American Society of Hypertension. 2007;1(1):30–44. [PubMed]
8. Sawyer DB. Oxidative stress in heart failure: what are we missing? American Journal of the Medical Sciences. 2011;342(2):120–124. [PMC free article] [PubMed]
9. De Los Santos R, Seidenfeld JJ, Anzueto A, et al. One hundred percent oxygen lung injury in adult baboons. American Review of Respiratory Disease. 1987;136(3):657– 661. [PubMed]
10. Howden R, Cho HY, Miller-DeGraff L, et al. Cardiac physiologic and genetic predictors of hyperoxia-induced acute lung injury in mice. American Journal of Respiratory Cell and Molecular Biology. 2012;46(4):470–478. [PMC free article] [PubMed]
11. Harrison RM, Yin J. Particulate matter in the atmosphere: which particle properties are important for its effects on health? Science of the Total Environment. 2000;249(1–3):85–101. [PubMed]
12. Wang T, Moreno-Vinasco L, Huang Y, et al. Murine lung response to ambient particulate matter: genomic analysis and influence on airway hyperresponsiveness. Environmental Health Perspectives. 2008;116(11):1500–1508. [PMC free article] [PubMed]
13. Dick CAJ, Singh P, Daniels M, Evansky P, Becker S, Gilmour MI. Murine pulmonary inflammatory responses following instillation of size-fractionated ambient particulate matter. Journal of Toxicology and Environmental Health A. 2003;66(23):2193–2207. [PubMed]
14. Budinger GRS, McKell JL, Urich D, et al. Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms. PLoS ONE. 2011;6(4)e18525 [PMC free article] [PubMed]
15. Sun Q, Hong X, Wold LE. Cardiovascular effects of ambient particulate air pollution exposure. Circulation. 2010;121(25):2755–2765. [PMC free article] [PubMed]
16. Brook RD, Rajagopalan S, Pope CA, III, et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation. 2010;121(21):2331–2378. [PubMed]
17. Delfino RJ, Sioutas C, Malik S. Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health. Environmental Health Perspectives. 2005;113(8):934–946. [PMC free article] [PubMed]
18. Nelin TD, Joseph AM, Gorr MW, Wold LE. Direct and indirect effects of particulate matter on the cardiovascular system. Toxicology Letters. 2012;208(3):293–299. [PMC free article] [PubMed]
19. Langrish JP, Bosson J, Unosson J, et al. Cardiovascular effects of particulate air pollution exposure: time course and underlying mechanisms. Journal of Internal Medicine. 2012;272(3):224–239. [PubMed]
20. Bagaté K, Meiring JJ, Cassee FR, Borm PJA. The effect of particulate matter on resistance and conductance vessels in the rat. Inhalation Toxicology. 2004;16(6-7):431–436. [PubMed]
21. Schwartz PJ, Stone HL. The role of the autonomic nervous system in sudden coronary death. Annals of the New York Academy of Sciences. 1982;382:162–180. [PubMed]
22. Watkinson WP, Campen MJ, Nolan JP, Costa DL. Cardiovascular and systemic responses to inhaled pollutants in rodents: effects of Ozone and particulate matter. Environmental Health Perspectives. 2001;109(4):539–546. [PMC free article] [PubMed]
23. Whitsel EA, Quibrera PM, Christ SL, et al. Heart rate variability, ambient particulate matter air pollution, and glucose homeostasis: the environmental epidemiology of arrhythmogenesis in the Women’s Health Initiative. American Journal of Epidemiology. 2009;169(6):693–703. [PMC free article] [PubMed]
24. Cavallari JM, Fang SC, Eisen EA, et al. Time course of heart rate variability decline following particulate matter exposures in an occupational cohort. Inhalation Toxicology. 2008;20(4):415–422. [PubMed]
25. Suwa T, Hogg JC, Quinlan KB, Ohgami A, Vincent R, Van Eeden SF. Particulate air pollution induces progression of atherosclerosis. Journal of the American College of Cardiology. 2002;39(6):935–942. [PubMed]
26. Gong KW, Zhao W, Li N, et al. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells. Genome Biology. 2007;8(7, article R149) [PMC free article] [PubMed]
27. Nemmar A, Hoet PHM, Vanquickenborne B, et al. Passage of inhaled particles into the blood circulation in humans. Circulation. 2002;105(4):411–414. [PubMed]
28. Terzano C, Di Stefano F, Conti V, Graziani E, Petroianni A. Air pollution ultrafine particles: toxicity beyond the lung. European Review for Medical and Pharmacological Sciences. 2010;14(10):809–821. [PubMed]
29. Mills NL, Donaldson K, Hadoke PW, et al. Adverse cardiovascular effects of air pollution. Nature Clinical Practice Cardiovascular Medicine. 2009;6(1):36–44. [PubMed]
30. Muto E, Hayashi T, Yamada K, Esaki T, Sagai M, Iguchi A. Endothelial-constitutive nitric oxide synthase exists in airways and diesel exhaust particles inhibit the effect of nitric oxide. Life Sciences. 1996;59(18):1563–1570. [PubMed]
31. Bai Y, Suzuki AK, Sagai M. The cytotoxic effects of diesel exhaust particles on human pulmonary artery endothelial cells in vitro: role of active oxygen species. Free Radical Biology and Medicine. 2001;30(5):555–562. [PubMed]
32. Okayama Y, Kuwahara M, Suzuki A, Tsubone H. Role of reactive oxygen species on diesel exhaust particle-induced cytotoxicity in rat cardiac myocytes. Journal of Toxicology and Environmental Health A. 2006;69(18):1699–1710. [PubMed]
33. Zuo L, Youtz DJ, Wold LE. Particulate matter exposure exacerbates high glucose-induced cardiomyocyte dysfunction through ROS generation. PLoS ONE. 2011;6(8)e23116 [PMC free article] [PubMed]
34. Cho HY, Jedlicka AE, Reddy SPM, et al. Role of NRF2 in protection against hyperoxic lung injury in mice. American Journal of Respiratory Cell and Molecular Biology. 2002;26(2):175–182. [PubMed]
35. Cho HY, Jedlicka AE, Reddy SPM, Zhang LY, Kensler TW, Kleeberger SR. Linkage analysis of susceptibility to hyperoxia NRF2 is a candidate gene. American Journal of Respiratory Cell and Molecular Biology. 2002;26(1):42–51. [PubMed]
36. Li N, Alam J, Venkatesan MI, et al. NRF2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals. Journal of Immunology. 2004;173(5):3467–3481. [PubMed]
37. Parrish DA, Mitchell BC, Henson PM, Larsen GL. Pulmonary response of fifth component of complement-sufficient and -deficient mice to hyperoxia. Journal of Clinical Investigation. 1984;74(3):956–965. [PMC free article] [PubMed]
38. Johnston CJ, Mango GW, Finkelstein JN, Stripp BR. Altered pulmonary response to hyperoxia in clara cell secretory protein deficient mice. American Journal of Respiratory Cell and Molecular Biology. 1997;17(2):147–155. [PubMed]
39. Zanobetti A, Baccarelli A, Schwartz J. Gene-air pollution interaction and cardiovascular disease: a review. Progress in Cardiovascular Diseases. 2011;53(5):344–352. [PMC free article] [PubMed]
40. Chuang KJ, Chan CC, Su TC, Lee CT, Tang CS. The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults. American Journal of Respiratory and Critical Care Medicine. 2007;176(4):370–376. [PubMed]
41. Chahine T, Baccarelli A, Litonjua A, et al. Particulate air pollution, oxidative stress genes, and heart rate variability in an elderly cohort. Environmental Health Perspectives. 2007;115(11):1617–1622. [PMC free article] [PubMed]
42. Rhoden CR, Wellenius GA, Ghelfi E, Lawrence J, González-Flecha B. PM-induced cardiac oxidative stress and dysfunction are mediated by autonomic stimulation. Biochimica et Biophysica Acta. 2005;1725(3):305–313. [PubMed]
43. Itoh K, Chiba T, Takahashi S, et al. An NRF2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical Research Communications. 1997;236(2):313–322. [PubMed]
44. Becker S, Dailey LA, Soukup JM, Grambow SC, Devlin RB, Huang YCT. Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress. Environmental Health Perspectives. 2005;113(8):1032–1038. [PMC free article] [PubMed]
45. Howden R, Liu E, Miller-DeGraff L, et al. The genetic contribution to heart rate and heart rate variability in quiescent mice. American Journal of Physiology. 2008;295(1):H59–H68. [PubMed]
46. Huang YCT, Karoly ED, Dailey LA, et al. Comparison of gene expression profiles induced by coarse, fine, and ultrafine particulate matter. Journal of Toxicology and Environmental Health A. 2011;74(5):296–312. [PubMed]
47. Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. Journal of Clinical Investigation. 2005;115(3):500–508. [PMC free article] [PubMed]
48. Ferrari R, Alfieri O, Curello S, et al. Occurrence of oxidative stress during reperfusion of the human heart. Circulation. 1990;81(1):201–211. [PubMed]
49. Gurgueira SA, Lawrence J, Coull B, Krishna Murthy GG, González-Flecha B. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation. Environmental Health Perspectives. 2002;110(8):749–755. [PMC free article] [PubMed]
50. Bennett BA, Mitzner W, Tankersley CG. The effects of age and carbon black on airway resistance in mice. Inhalation Toxicology. 2012;24(14):931–938. [PubMed]
51. Boezen HM, Vonk JM, van der Zee SC, et al. Susceptibility to air pollution in elderly males and females. European Respiratory Journal. 2005;25(6):1018–1024. [PubMed]
52. Peters A, Dockery DW, Heinrich J, Wichmann HE. Short-term effects of particulate air pollution on respiratory morbidity in asthmatic children. European Respiratory Journal. 1997;10(4):872–879. [PubMed]
53. Pope CA, Burnett RT, Thurston GD, et al. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation. 2004;109(1):71–77. [PubMed]
54. Schwartz J. PM10, ozone, and hospital admissions for the elderly in Minneapolis-St. Paul, Minnesota. Archives of Environmental Health. 1994;49(5):366–374. [PubMed]
55. Miller MR, Shaw CA, Langrish JP. From particles to patients: oxidative stress and the cardiovascular effects of air pollution. Future Cardiology. 2012;8(4):577–602. [PubMed]
56. Pope C. Flying high. Alan J. Beason, FACMPE, MGMA member and chief executive officer, Cardiovascular Consultants LLP, Shreveport, La. MGMA Connexion/Medical group Management Association. 2004;4(6):p. 60. [PubMed]
57. Hudak BB, Zhang LY, Kleeberger SR. Inter-strain variation in susceptibility to hyperoxic injury of murine airways. Pharmacogenetics. 1993;3(3):135–143. [PubMed]
58. Whitehead GS, Burch LH, Berman KG, Piantadosi CA, Schwartz DA. Genetic basis of murine responses to hyperoxia-induced lung injury. Immunogenetics. 2006;58(10):793–804. [PMC free article] [PubMed]
59. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Annals of Internal Medicine. 2004;141(6):460–470. [PubMed]
60. Poets CF, Stebbens VA, Samuels MP, Southall DP. The relationship between bradycardia, apnea, and hypoxemia in preterm infants. Pediatric Research. 1993;34(2):144–147. [PubMed]
61. Butler PJ. Effect of progressive hypoxia on the respiratory & cardiovascular system of chickens. Journal of Physiology. 1967;191(2):309–324. [PubMed]
62. Zwillich C, Devlin T, White D. Bradycardia during sleep apnea. Characteristics and mechanism. Journal of Clinical Investigation. 1982;69(6):1286–1292. [PMC free article] [PubMed]
63. Malpas SC. Neural influences on cardiovascular variability: possibilities and pitfalls. American Journal of Physiology. 2002;282(1):H6–H20. [PubMed]
64. Wang L, Gallagher EP. Role of NRF2 antioxidant defense in mitigating cadmium-induced oxidative stress in the olfactory system of zebrafish. Toxicology and Applied Pharmacology. 2013;266(2):177–186. [PubMed]
65. Avilov OV, Sudakov KV. Effects of olfactory stimuli on students with various tones of the autonomic nervous system. Fiziologiia Cheloveka. 2008;34(6):63–69. [PubMed]
66. Oberdörster G, Sharp Z, Atudorei V, et al. Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicology. 2004;16(6-7):437–445. [PubMed]
67. Tsutsui K, Manabe RI, Yamada T, et al. ADAMTSL-6 is a novel extracellular matrix protein that binds to fibrillin-1 and promotes fibrillin-1 fibril formation. Journal of Biological Chemistry. 2010;285(7):4870–4882. [PMC free article] [PubMed]
68. Ramirez F, Dietz HC. Marfan syndrome: from molecular pathogenesis to clinical treatment. Current Opinion in Genetics and Development. 2007;17(3):252–258. [PubMed]
69. Bouzeghrane F, Reinhardt DP, Reudelhuber TL, Thibault G. Enhanced expression of fibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis. American Journal of Physiology. 2005;289(3):H982–H991. [PubMed]
70. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part II. Causal mechanisms and treatment. Circulation. 2002;105(12):1503–1508. [PubMed]
71. Cho HY, Reddy SP, DeBiase A, Yamamoto M, Kleeberger SR. Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radical Biology and Medicine. 2005;38(3):325–343. [PubMed]

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