The pathological roles of environmental and redox stresses in cardiovascular diseases
Environ Health Prev Med
The pathological roles of environmental and redox stresses in cardiovascular diseases
Sahoko Ichihara 0
0 S. Ichihara (&) Graduate School of Regional Innovation Studies, Mie University , 1577 Kurimamachiya-cho, Tsu 514-8507 , Japan
Oxidative stress and inflammation are implicated in cardiovascular diseases such as atherosclerosis, reperfusion injury, hypertension, and heart failure. High levels of oxidative stress resulting from increased cardiac generation of reactive oxygen species (ROS) is thought to contribute to contractile and endothelial dysfunction, apoptosis and necrosis of myocytes, and extracellular matrix remodeling in the heart. ROS activate several transcription factors known as redox-regulated transcription factors, and these transcription factors play important roles in the pathophysiology of cardiovascular diseases. This review focuses on the pathological roles of environmental and redox stresses in cardiovascular diseases, especially severe cardiac dysfunction and the transition from compensated hypertrophy to heart failure. The aryl hydrocarbon receptor (AHR) and NF-E2 p45-related factor (Nrf2) are transcription factors involved in the regulation of drug-metabolizing enzymes. AHR has been studied as a receptor for environmental contaminants and as a mediator of chemical toxicity. However, other roles for AHR in cardiac and vascular development have recently been described. Moreover, Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes. The roles of these transcription factors, AHR and Nrf2 in angiogenesis are also discussed in this review.
Environmental cardiology; Redox-regulated transcription factors mechanisms; Cardiovascular diseases; Oxidative stress; Molecular
Reactive oxygen species (ROS) are implicated in ailments
of the cardiovascular system, such as atherosclerosis,
reperfusion injury, hypertension, and heart failure [
Increased oxidative stress resulting from the
overproduction of ROS or low levels of available antioxidants is
thought to contribute to contractile and endothelial
dysfunction, apoptosis and necrosis of myocytes, and
remodeling of the extracellular matrix in the myocardium .
Such oxidative stress has indeed been demonstrated in
patients with various hypertensive disorders [
] as well as
in animal models of heart failure [
Roles of oxidative stress in cardiac dysfunction
Chronic heart failure is characterized by chronically and
tonically enhanced sympathetic tone and
], leading to left ventricular (LV) dysfunction.
Downregulation and desensitization of b-adrenergic
receptor signaling is a major contributing factor in the contractile
dysfunction of the failing heart. Certain b-blockers are
known to reduce the level of lipid peroxidation evident in the
myocardium of patients with dilated cardiomyopathy
] and to inhibit the upregulation of the DNA
binding activities of redox-regulated transcription factors in
neonatal rat cardiac ventricular myocytes [
that one of the beneficial effects of b-blockers in individuals
with heart failure is attenuation of oxidative stress. In
addition, superoxide production or biochemical markers of
oxidative stress are increased in individuals with severe
heart failure [
]. Oxidative stress is therefore an important
susceptibility factor for cardiac dysfunction, and agents that
reduce the level of such stress or interfere with the
generation of intracellular ROS are potentially suitable for
the treatment of chronic heart failure [
To determine the kinetics of the onset and progression of
LV dysfunction resulting in heart failure in TO-2 hamsters
(an appropriate model of DCM), we characterized the serial
changes in LV function and structure by echocardiography
and histological analysis, as well as by the extent of
oxidative stress and b-adrenergic signaling in the LV
]. As shown in Fig. 1A, LV dysfunction
first appeared at 8 weeks of age and deteriorated thereafter
in TO-2 hamsters. Compared with the control, the
glutathione redox ratio in the LV myocardium of TO-2 hamsters
increased (indicating oxidative stress) at 4 weeks and
became significantly higher after 8 weeks (Fig. 1B). The
hearts of TO-2 hamsters had significantly lower levels of
superoxide dismutase (SOD) activity from 8 weeks onward
compared with the control hamsters (Fig. 1C). Moreover,
adenylyl cyclase activity was significantly lower in the LV
myocardium at 18 weeks (Fig. 1D). These observations
indicated that myocardial oxidative stress was actually
enhanced in the initial development of LV dysfunction.
Both the activation of myocardial oxidative stress and
impairment of b-adrenergic signaling became prominent at
the stage of severe LV dysfunction, suggesting the
involvement of myocardial oxidative stress in the
development of b-adrenergic desensitization, leading to cardiac
Doxorubicin (DOX) is one of the most widely used
drugs in the treatment of a variety of human neoplasms
]. However, long-term treatment with DOX can result in
Fig. 1 Serial changes in left ventricular (LV) function and extent of
oxidative stress in TO-2 and control hamsters. A Representative
echocardiograms and representative light photomicrographs of LV
cross-sections stained with hematoxylin–eosin. B–D Glutathione
redox ratio (GSH/GSSG; oxidized glutathione/reduced glutathione)
(B), superoxide dismutase (SOD) enzyme activity (C), and adenylyl
cyclase (AC) activity (D) in the LV myocardium. Data are
mean ± standard error of the mean (SEM) of 8 animals in each
experiment. *P \ 0.05 versus age-matched controls
the development of cardiomyopathy and congestive heart
failure in a process that involves multiple factors,
including the generation of free radicals that damage
cellular membranes [
], disturbance of adrenergic
function, alterations in intracellular Ca2? homeostasis
, myocardial cell apoptosis [
], and selective
inhibition of the expression of cardiac muscle-specific
]. We investigated the mechanism of
DOXinduced cardiotoxicity in mice as well as whether
polyethylene glycol-conjugated SOD (PEG-SOD) protects
against such toxicity. PEG-SOD is a membrane-permeable
antioxidant with a long half-life in plasma [
pretreatment with this conjugate has been reported to
protect against reperfusion-induced arrhythmias as well as
myocardial ischemia–reperfusion injury in animal models
]. Our results demonstrated that DOX-induced
cardiotoxicity was associated with increased oxidative
stress, apoptosis, and impaired angiogenesis in the left
ventricle of mice . Furthermore, treatment with
PEGSOD ameliorated DOX-induced cardiac dysfunction, and
this effect was mediated through inhibition of
DOXinduced upregulation of nuclear factor-jB (NF-jB)
signaling, lowering the levels of hexanoyl-lysine (HEL), a
marker of free radical-induced lipid peroxidation, and
suppression of the activation of Akt and Akt-regulated
gene expression [
]. These results suggested that the
antioxidant PEG-SOD prevented cardiac dysfunction
induced by DOX through normalization of oxidative stress
and redox-regulated NF-jB signaling.
Association between cardiac function and regulation of redox-regulated transcription factors
Reactive oxygen species activate several transcription
factors, including NF-jB, activator protein-1 (AP-1), early
growth response gene-1 (Egr-1), surfactant protein 1
(SP1), and E26 transformation specific-1 (Ets-1) [
binding sites for NF-jB and AP-1 are present in the
promoter regions of various genes that are important in
the pathogenesis of cardiovascular diseases [
Expression of Egr-1 is the highest in the brain and heart and is
increased in the intact heart or neonatal cardiomyocytes
following stimulation with endothelin, angiotensin II, and
]. SP1 and Ets-1 are expressed in a variety of
cell types, including endothelial cells, vascular smooth
muscle cells, and cardiomyocytes, and they regulate the
transcription of several genes that function in
angiogenesis or remodeling of the extracellular matrix [
Peroxisome proliferator-activated receptor-a (PPAR-a)
belongs to the nuclear receptor superfamily and
contributes to the regulation of the expression of genes for
transport proteins and enzymes that participate in fatty
acid and triglyceride metabolism [
]. PPAR-a is
expressed in cells of the cardiovascular system, including
endothelial cells, vascular smooth muscle cells,
monocytes–macrophages, and cardiomyocytes [
results of several recent animal studies have suggested
the substantial involvement of PPAR-a deactivation in the
phenotypic changes that accompany cardiac growth in
conditions of pressure overload, and that a compromised
PPAR-a activity may participate in the deterioration of
compensated LV hypertrophy to heart failure in
hypertensive heart disease [
]. Furthermore, Gomez-Garre
et al.  have shown that PPAR-a and PPAR-c are
selectively activated in the atria of patients with end-stage
heart failure and might be functionally important in the
maintenance of atrial morphology. We investigated the
effects of fenofibrate, a ligand and activator of PPAR-a,
on the development of myocardial hypertrophy and
progression from compensated LV hypertrophy to heart
failure in Dahl salt-sensitive (DS) rats [
]. In the same
study we also examined the effects of this substance on
the inflammatory response and on the activities of
redoxregulated transcription factors in the heart of these
animals. DS rats fed a high-salt diet developed cardiac
hypertrophy at 12 weeks of age, but this was significantly
attenuated in rats treated with fenofibrate. At 18 weeks of
age, the LV end-diastolic diameter was significantly
greater in rats fed the high-salt diet than in rats fed the
low-salt diet, but this was significantly attenuated in rats
treated with fenofibrate. A marked increase in the extent
of interstitial fibrosis in the left ventricle was noted in
18-week-old rats fed the high-salt diet compared to rats
fed the low-salt diet (Fig. 2A). This increase in cardiac
fibrosis was greatly reduced by treatment with both
lowand high-dose fenofibrate. Infiltration of macrophages and
T lymphocytes into the left ventricle was also pronounced
in rats fed the high-salt diet compared with those fed the
low-salt diet, and the accumulation of such cells was
again suppressed by fenofibrate (Fig. 2A). Furthermore,
the DNA binding activities of NF-jB and AP-1 were
significantly higher in rats fed the high-salt diet compared
with those fed the low-salt diet. Treatment with both
lowand high-dose fenofibrate resulted in a significant
reduction in the DNA binding activities of these transcription
factors (Fig. 2B, C). The PPAR-a activator fenofibrate
attenuated the progression of heart failure and improved
the survival rate in this rat model. These effects were
associated with inhibition of the inflammatory response
and suppression of activation of redox-regulated
transcription factors in the left ventricle. The findings
suggested that PPAR-a seems to function as a modulator of
inflammation in the heart and that its activation may have
beneficial effects on cardiac metabolism and function in
normal and diseased states.
Arrows Infiltrated immunoreactive cells. B Representative
electrophoretic mobility-shift assays for the binding activities of nuclear factor-jB
(NF-jB) and activator protein-1 (AP-1). Lanes: a Free extracts, b
lowsalt diet group, c high-salt diet group, d high-salt diet ? PPARa Act
(low) group, e high-salt diet ? PPARa Act (high) group, f cold probe.
C Quantitative data expressed relative to the corresponding value of the
low-salt diet group. Results are presented as the mean ± SEM of 4
animals in each experiment. *P \ 0.05 vs. rats fed the low-salt diet,
P \ 0.05 vs. rats fed the high-salt diet and treated with vehicle
Environmental stress responses in cardiovascular diseases
Cigarette smoking is a major risk factor for ischemic heart
disease, peripheral vascular disease, and chronic
obstructive pulmonary disease [
]. It has adverse effects on
vascular biology, inducing endothelial dysfunction and
arterial stiffness , and it inhibits angiogenesis by
pulmonary artery endothelial cells in the setting of severe
vascular obstruction and lung tissue ischemia [
effects of benzo[a]pyrene (B[a]P) in cigarette smoking and
of other polycyclic and halogenated aromatic hydrocarbons
in the environment are mediated by the aryl hydrocarbon
receptor (AHR) . The ligand-bound form of the AHR
and AHR nuclear translocator (ARNT), which belongs to
the Per–Arnt–Sim (PAS) family of basic helix–loop–helix
transcription factors, form a heterodimeric transcription
] which binds to the xenobiotic response elements
(XREs) in the promoter regions of the target genes, such as
that encoding cytochrome P450 1A1 (CYP1A1) [
Activation of vascular endothelial growth factor (VEGF) is
mediated by the binding of another basic helix–loop–helix
transcription factor, hypoxia-inducible factor-1a (HIF-1a)
], which also dimerizes with ARNT [
]. To examine
the effects of cigarette smoking on angiogenesis, we treated
mice with B[a]P, one of the polycyclic and halogenated
aromatic hydrocarbons found in tobacco smoke, in an
animal model in which ischemia was induced surgically in
a hindlimb [
]. Oral exposure to B[a]P resulted in
significant inhibition of ischemia-induced increase in
hindlimb blood flow in wild-type mice (Fig. 3A, B). AHR
deficiency attenuated the inhibition of ischemia-induced
angiogenesis by B[a]P, and the B[a]P-induced increase in
the amount of CYP1A1 mRNA in wild-type mice was not
apparent in AHR-null mice. Ischemia-induced
angiogenesis was markedly enhanced in AHR-null mice compared
with that in wild-type animals [
upregulation of the expression of HIF-1a and ARNT, as
well as that of target genes for these transcription factors,
such as that for VEGF, were also enhanced in AHR-null
Fig. 3 Changes in blood flow ratio after arterial ligation in the left
hindlimb of aryl hydrocarbon receptor (AHR)-null or wild-type (WT)
mice exposed to benzo[a]pyrene (B[a]P) or vehicle. A Laser Doppler
perfusion imaging of blood flow immediately and 4 weeks after
surgery and the commencement of weekly administration of B[a]P
(125 mg/kg) or vehicle. B The ratio of blood flow in the ischemic
(left) hindlimb to that in the normal (right) hindlimb measured
immediately and each week after surgery and the commencement of
weekly administration of B[a]P or vehicle. All quantitative data are
given as the mean ± SEM of values from 8 mice per group.
*P \ 0.05 vs. corresponding value for vehicle-treated WT mice,
P \ 0.05 vs. corresponding value for B[a]P-treated WT mice.
C Representative immunoblot (IB) analysis of hypoxia-inducible
factor-1a (HIF-1a), AHR nuclear translocator (ARNT), and lamin
(loading control) in nuclear extracts, and vascular endothelial growth
factor (VEGF) in ischemic or non-ischemic tissue at 1 week after
surgery. D Quantitative data of the DNA binding activity of HIF-1a–
ARNT in nuclear extracts of tissue isolated 1 week after surgery. All
data are mean ± SEM of values from 6 mice per group. *P \ 0.05
vs. non-ischemic hindlimb of WT mice; P \ 0.05 vs. non-ischemic
hindlimb of AHR-null mice, P \ 0.05 vs. ischemic hindlimb of
mice (Fig. 3C). Furthermore, both the DNA binding
activity of the HIF-1a–ARNT complex (Fig. 3D) and the
association of HIF-1a and ARNT with the VEGF gene
promoter were increased by ischemia to a greater extent in
AHR-null mice than in wild-type mice, suggesting that
AHR–ARNT signaling plays an important role in the
regulation of ischemia-induced angiogenesis [
The transcription factor Nrf2 [nuclear factor-erythroid 2
(NF-E2)-related factor 2; also known as NF-E2 like 2
(Nfe2l2)] is a member of the NF-E2 basic-leucine zipper
family of proteins and interacts with the antioxidant
response element (ARE) that is present in the promoter
regions of genes for phase 2 detoxifying enzymes [
also protects against oxidative stress through
ARE-mediated transcriptional activation of the genes for several
antioxidant enzymes [
]. Nrf2 signaling was reported to
protect against renal oxidative damage induced by ferric
], mitochondrial complex II
inhibitormediated neurotoxicity [
], and pulmonary hyperoxic
]. Moreover, genetic ablation of Nrf2 was found
to increase susceptibility to severe airway inflammation
and to cigarette smoke-induced emphysema in mice [
]. Our group investigated the potential role of Nrf2 in
neovascularization with a murine surgical model of
ischemia . Nrf2-deficient animals (mice lacking the
transcription factor Nrf2) showed markedly enhanced
ischemia-induced neovascularization, underexpression of
Nrf2 target genes encoding antioxidant enzymes, and
potentiated inflammatory response [
]. The promotion of
neovascularization by Nrf2 deficiency may thus be
attributed to the enhanced inflammatory response resulting from
impaired antioxidant defense and ROS accumulation in
Conclusion and future perspectives
Increased oxidative stress is implicated in the pathogenesis
of heart failure, and inflammation is thought to play an
important role in the progression of cardiovascular
diseases. Myocardial oxidative stress is actually enhanced
even at the initial stages of LV dysfunction. Treatments
that reduce the level of inflammation promoted by
activating the redox-regulated transcription factors are thus
important to improve hemodynamic function in patients
with advanced heart failure.
Heart diseases develop as a result of complex
interactions between genes and environment. Although we
demonstrated the significant associations of gene
polymorphisms with cardiovascular diseases [
odds ratio for the effect of the genotype of susceptibility
genes to cardiovascular diseases was only moderate. This
evidence suggests that large subsets of genes involved in
many processes, such as blood pressure regulation,
cholesterol metabolism, insulin sensitivity, redox signaling,
antioxidant defense, and inflammation, contribute to the
risk of complex traits, such as cardiovascular diseases.
Since lifestyle choices, such as smoking, diet, and exercise,
are considered to be key factors in cardiovascular diseases,
exposure to pollutants and environmental chemicals could
elevate the risk of cardiovascular diseases. In fact,
exposure to fine particles, arsenic, lead, cadmium, solvents, and
pesticides have been linked to increased incidence of
cardiovascular diseases . These effects might be attributed
to changes in the synthesis or reactivity of nitric oxide that
may be caused by environmental oxidants or increased
endogenous production of ROS [
]. To contribute to
the field of environmental cardiology, we need to elucidate
the underlying physiological and molecular mechanisms
and estimate the relative susceptibility of individuals for
Acknowledgments This study was supported in part by grants from
the Japan Society for the Promotion of Science, from the Takeda
Science Foundation, from the Astellas Foundation for Research on
Metabolic Disorders, and from the Suzuken Memorial Foundation.
Conflict of interest None.
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