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1.
J Cell Mol Med ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32383522

RESUMO

Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S-nitros(yl)ation by nitric oxide (NO) and its derivatives, and S-sulphydration by hydrogen sulphide (H2 S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2 S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed at decreasing mitochondrial ROS accumulation have been developed and have shown cardioprotective effects in experimental settings. However, ROS, NO and H2 S play also a role in endogenous cardioprotection, as in the case of ischaemic pre-conditioning, so that preventing their increase might hamper self-defence mechanisms. The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2 S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R. The elucidation of the signalling pathways of ROS, NO and H2 S is likely to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent I/R injury.

2.
Antioxidants (Basel) ; 9(5)2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384768

RESUMO

Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endothelial dysfunction and cardiovascular disease, but may also contribute to redox signaling. Therefore, their precise detection is important for the evaluation of disease mechanisms. Here, we compared three different methods for the detection of 3-nitrotyrosine (3-NT), a marker of nitro-oxidative stress, in biological samples. Nitrated proteins were generated by incubation with peroxynitrite or 3-morpholino sydnonimine (Sin-1) and subjected to total hydrolysis using pronase, a mixture of different proteases. The 3-NT was then separated by high performance liquid chromatography (HPLC) and quantified by electrochemical detection (ECD, CoulArray) and compared to classical methods, namely enzyme-linked immunosorbent assay (ELISA) and dot blot analysis using specific 3-NT antibodies. Calibration curves for authentic 3-NT (detection limit 10 nM) and a concentration-response pattern for 3-NT obtained from digested nitrated bovine serum albumin (BSA) were highly linear over a wide 3-NT concentration range. Also, ex vivo nitration of protein from heart, isolated mitochondria, and serum/plasma could be quantified using the HPLC/ECD method and was confirmed by LC-MS/MS. Of note, nitro-oxidative damage of mitochondria results in increased superoxide (O2•-) formation rates (measured by dihydroethidium-based HPLC assay), pointing to a self-amplification mechanism of oxidative stress. Based on our ex vivo data, the CoulArray quantification method for 3-NT seems to have some advantages regarding sensitivity and selectivity. Establishing a reliable automated HPLC assay for the routine quantification of 3-NT in biological samples of cell culture, of animal and human origin seems to be more sophisticated than expected.

3.
Gesundheitswesen ; 2020 Apr 30.
Artigo em Alemão | MEDLINE | ID: mdl-32356301

RESUMO

AIM: The aim of the article is to point out the important role of prevention and reduction of mental stress in the general population and in sensitive groups in the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This article includes the analysis and evaluation of studies and recommendations from organizations such as the World Health Organization (WHO) that have examined the psychological consequences of epidemics/pandemics on people and their impact on the further course. RESULTS: Fear-related behaviors can adversely affect the course of epidemics. Past outbreaks of infectious diseases (Ebola and Zika virus) have shown that maladaptive behavior, related to increased psychological stress and anxiety, can interfere with the implementation of treatment strategies and actions and can contribute to a further spread. Hereby, strategies for dealing with infectious diseases, that include the suppression of fear, can trigger a vicious circle in which fear and suppression mutually reinforce each other. CONCLUSION: The COVID-19 pandemic poses an immense challenge to governments, health systems and people, with an uncertain outcome, which is associated with a significant burden of mental health in the population. In line with WHO recommendations, national guidelines and preventive measures should include the psychological consequences, the acceptance and normalization of fears and the promotion of resilience in the population in dealing with COVID-19 in order to counteract a further spread.

4.
Int J Mol Sci ; 21(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408480

RESUMO

Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The general concept of redox-based activation of RONS sources via "kindling radicals" and enzyme-specific "redox switches" as well as the interaction with redox-sensitive inflammatory pathways are discussed. Here, we present evidence for the existence of such cross talk mechanisms in the setting of diabetes and critically assess their contribution to the severity of diabetic complications.

5.
Redox Biol ; : 101506, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32371009

RESUMO

Environmental pollution and non-chemical stressors such as mental stress or traffic noise exposure are increasingly accepted as health risk factors with substantial contribution to chronic noncommunicable diseases (e.g. cardiovascular, metabolic and mental). Whereas the mechanisms of air pollution-mediated adverse health effects are well characterized, the mechanisms of traffic noise exposure are not completely understood, despite convincing clinical and epidemiological evidence for a significant contribution of environmental noise to overall mortality and disability. The initial mechanism of noise-induced cardiovascular, metabolic and mental disease is well defined by the "noise reaction model" and consists of neuronal activation involving the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system, followed by a classical stress response via cortisol and catecholamines. Stress pathways are initiated by noise-induced annoyance and sleep deprivation/fragmentation. This review highlights the down-stream pathophysiology of noise-induced mental stress, which is based on an induction of inflammation and oxidative stress. We highlight the sources of reactive oxygen species (ROS) involved and the known targets for noise-induced oxidative damage. Part of the review emphasizes noise-triggered uncoupling/dysregulation of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and its central role for vascular dysfunction.

6.
Free Radic Res ; : 1-13, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32326776

RESUMO

Background: Large epidemiological studies point towards a link between the incidence of arterial hypertension, ischaemic heart disease, metabolic disease and exposure to traffic noise, supporting the role of noise exposure as an independent cardiovascular risk factor. We characterised the underlying molecular mechanisms leading to noise-dependent adverse effects on the vasculature and myocardium in an animal model of aircraft noise exposure and identified oxidative stress and inflammation as central players in mediating vascular and cardiac dysfunction. Here, we studied the impact of noise-induced oxidative DNA damage on vascular function in DNA-repair deficient 8-oxoguanine glycosylase knockout (Ogg1-/-) mice.Methods and results: Noise exposure (peak sound levels of 85 and mean sound level of 72 dB(A) applied for 4d) caused oxidative DNA damage (8-oxoguanine) and enhanced NOX-2 expression in C57BL/6 mice with synergistic increases in Ogg1-/- mice (shown by immunohistochemistry). A similar pattern was found for oxidative burst of blood leukocytes and other markers of oxidative stress (4-hydroxynonenal, 3-nitrotyrosine) and inflammation (cyclooxygenase-2). We observed additive impairment of noise exposure and genetic Ogg1 deficiency on endothelium-independent relaxation (nitroglycerine), which may be due to exacerbated oxidative DNA damage leading to leukocyte activation and oxidative aldehyde dehydrogenase inhibition.Conclusions: The finding that chronic noise exposure causes oxidative DNA damage in mice is worrisome since these potential mutagenic lesions could contribute to cancer progression. Human field studies have to demonstrate whether oxidative DNA damage is also found in urban populations with high levels of noise exposure as recently shown for workers with high occupational noise exposure.

7.
Clin Res Cardiol ; 2020 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-32306084

RESUMO

BACKGROUND: Environmental noise exposure has been associated with increased cardiovascular morbidity and mortality. Recently, noise annoyance was shown to induce atrial fibrillation, which was accompanied by significantly increased levels of midregional pro atrial natriuretic peptide (MR-proANP). Therefore, the aim of the present study was to analyze the association between noise annoyance, MR-proANP, incident cardiovascular events, and all-cause mortality. METHODS: Levels of MR-proANP were measured in the first 5000 participants of the population-based Gutenberg Health Study. Annoyance was assessed separately for aircraft, road traffic, railway, neighborhood, and industrial/construction noise during the day and sleep. RESULTS: In cross-sectional analyses, aircraft noise annoyance during day and sleep, industrial/construction noise annoyance during day, and railway noise annoyance during sleep were independently associated with increased levels of MR-proANP after multivariable adjustment. After a 5-year follow-up period, there were 43 cases of incident atrial fibrillation and 103 of incident cardiovascular disease (comprising atrial fibrillation, coronary artery disease, myocardial infarction, heart failure, or stroke). Moreover, there were 301 deaths after a mean follow-up of 7.42 ± 1.66 years. An odds ratio (OR) of 2.82 ([95% confidence interval (CI) 1.86; 4.35], p < 0.0001) for incident atrial fibrillation and an OR of 1.49 ([95% CI 1.13; 1.96], p = 0.0046) for incident cardiovascular disease per 1-standard deviation (SD) increase in MR-proANP levels were found. A 36% (hazard ratio: 1.36 [95% CI 1.19; 1.55], p < 0.0001) higher risk of death was found per 1-SD increase in MR-proANP levels. CONCLUSIONS: Noise annoyance may contribute to cardiovascular morbidity and mortality and is characterized by increased levels of MR-proANP.

8.
Redox Biol ; : 101515, 2020 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-32345536

RESUMO

Arterial hypertension is the most important risk factor for the development of cardiovascular disease. Recently, aircraft noise has been shown to be associated with elevated blood pressure, endothelial dysfunction, and oxidative stress. Here, we investigated the potential exacerbated cardiovascular effects of aircraft noise in combination with experimental arterial hypertension. C57BL/6J mice were infused with 0.5 mg/kg/d of angiotensin II for 7 days, exposed to aircraft noise for 7 days at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A), or subjected to both stressors. Noise and angiotensin II increased blood pressure, endothelial dysfunction, oxidative stress and inflammation in aortic, cardiac and/or cerebral tissues in single exposure models. In mice subjected to both stressors, most of these risk factors showed potentiated adverse changes. We also found that mice exposed to both noise and ATII had increased phagocytic NADPH oxidase (NOX-2)-mediated superoxide formation, immune cell infiltration (monocytes, neutrophils and T cells) in the aortic wall, astrocyte activation in the brain, enhanced cytokine signaling, and subsequent vascular and cerebral oxidative stress. Exaggerated renal stress response was also observed. In summary, our results show an enhanced adverse cardiovascular effect between environmental noise exposure and arterial hypertension, which is mainly triggered by vascular inflammation and oxidative stress. Mechanistically, noise potentiates neuroinflammation and cerebral oxidative stress, which may be a potential link between both risk factors. The results indicate that a combination of classical (arterial hypertension) and novel (noise exposure) risk factors may be deleterious for cardiovascular health.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32245334

RESUMO

Significance: According to the World Health Organization, noncommunicable diseases are the globally leading cause of mortality. Recent Advances: About 71% of 56 million deaths that occurred worldwide are due to noncommunicable cardiovascular risk factors, including tobacco smoking, unhealthy diets, lack of physical activity, overweight, arterial hypertension, diabetes, and hypercholesterolemia, which can be either avoided or substantially reduced. Critical Issues: Thus, it is estimated that 80% of premature heart disease, stroke, and diabetes can be prevented. More recent evidence indicates that environmental stressors such as noise and air pollution contribute significantly to the global burden of cardiovascular disease. In the present review, we focus primarily on important environmental stressors such as transportation noise and air pollution. We discuss the pathophysiology of vascular damage caused by these environmental stressors, with emphasis on early subclinical damage of the vasculature such as endothelial dysfunction and the role of oxidative stress. Future Directions: Lower legal thresholds and mitigation measures should be implemented and may help to prevent vascular damage.

10.
Free Radic Biol Med ; 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32131026

RESUMO

According to the latest Global Burden of Disease Study data, non-communicable diseases in general and cardiovascular disease (CVD) in particular are the leading cause of premature death and reduced quality of life. Demographic shifts, unhealthy lifestyles and a higher burden of adverse environmental factors provide an explanation for these findings. The expected growing prevalence of CVD requires enhanced research efforts for identification and characterisation of novel therapeutic targets and strategies. Cardiovascular risk factors including classical (e.g. hypertension, diabetes, hypercholesterolaemia) and non-classical (e.g. environmental stress) factors induce the development of endothelial dysfunction, which is closely associated with oxidant stress and vascular inflammation and results in CVD, particularly in older adults. Most classically successful therapies for CVD display vasoprotective, antioxidant and anti-inflammatory effects, but were originally designed with other therapeutic aims. So far, only a few 'redox drugs' are in clinical use and many antioxidant strategies have not met expectations. With the present review, we summarise the actual knowledge on CVD pathomechanisms, with special emphasis on endothelial dysfunction, adverse redox signalling and oxidative stress, highlighting the preclinical and clinical evidence. In addition, we provide a brief overview of established CVD therapies and their relation to endothelial dysfunction and oxidative stress. Finally, we discuss novel strategies for redox-based CVD therapies trying to explain why, despite a clear link between endothelial dysfunction and adverse redox signalling and oxidative stress, redox- and oxidative stress-based therapies have not yet provided a breakthrough in the treatment of endothelial dysfunction and CVD.

11.
Eur Heart J ; 41(15): 1524, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32211878
12.
Eur Heart J ; 41(15): 1526, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32077936
13.
Arterioscler Thromb Vasc Biol ; 40(3): e65-e77, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31893947

RESUMO

OBJECTIVE: In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4-/-), but not of GLP-1-receptors (Glp1r-/-), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced upon ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role. CONCLUSIONS: Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets.

14.
Eur Heart J ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899473

RESUMO

AIMS: In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. METHODS AND RESULTS: The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group. CONCLUSION: As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. EUDRACT-NO: 2011-005305-73.

15.
Annu Rev Public Health ; 41: 309-328, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-31922930

RESUMO

Exposure to traffic noise is associated with stress and sleep disturbances. The World Health Organization (WHO) recently concluded that road traffic noise increases the risk for ischemic heart disease and potentially other cardiometabolic diseases, including stroke, obesity, and diabetes. The WHO report focused on whole-day noise exposure, but new epidemiological and translational field noise studies indicate that nighttime noise, in particular,is an important risk factor for cardiovascular disease (CVD) through increased levels of stress hormones and vascular oxidative stress, leading to endothelial dysfunction and subsequent development of various CVDs. Novel experimental studies found noise to be associated with oxidative stress-induced vascular and brain damage, mediated by activation of the NADPH oxidase, uncoupling of endothelial and neuronal nitric oxide synthase, and vascular/brain infiltration with inflammatory cells. Noise-induced pathophysiology was more pronounced in response to nighttime as compared with daytime noise. This review focuses on the consequences of nighttime noise.

16.
Arterioscler Thromb Vasc Biol ; 40(1): 145-158, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31747801

RESUMO

OBJECTIVE: Cardiovascular outcome trials demonstrated that GLP-1 (glucagon-like peptide-1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus. Whether GLP-1 analogs reduce the risk for atherosclerosis independent of glycemic control is challenging to elucidate as the GLP-1R (GLP-1 receptor) is expressed on different cell types, including endothelial and immune cells. Approach and Results: Here, we reveal the cardio- and vasoprotective mechanism of the GLP-1 analog liraglutide at the cellular level in a murine, nondiabetic model of arterial hypertension. Wild-type (C57BL/6J), global (Glp1r-/-), as well as endothelial (Glp1rflox/floxxCdh5cre) and myeloid cell-specific knockout mice (Glp1rflox/floxxLysMcre) of the GLP-1R were studied, and arterial hypertension was induced by angiotensin II. Liraglutide treatment normalized blood pressure, cardiac hypertrophy, vascular fibrosis, endothelial dysfunction, oxidative stress, and vascular inflammation in a GLP-1R-dependent manner. Mechanistically, liraglutide reduced leukocyte rolling on the endothelium and infiltration of myeloid Ly6G-Ly6C+ and Ly6G+Ly6C+ cells into the vascular wall. As a consequence, liraglutide prevented vascular oxidative stress, reduced S-glutathionylation as a marker of eNOS (endothelial NO synthase) uncoupling, and increased NO bioavailability. Importantly, all of these beneficial cardiovascular effects of liraglutide persisted in myeloid cell GLP-1R-deficient (Glp1rflox/floxxLysMcre) mice but were abolished in global (Glp1r-/-) and endothelial cell-specific (Glp1rflox/floxxCdh5cre) GLP-1R knockout mice. CONCLUSIONS: GLP-1R activation attenuates cardiovascular complications of arterial hypertension by reduction of vascular inflammation through selective actions requiring the endothelial but not the myeloid cell GLP-1R.

18.
Oxid Med Cell Longev ; 2019: 4623109, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814877

RESUMO

The role of noise as an environmental pollutant and its adverse effects on health are being increasingly recognized. Beyond its direct effects on the auditory system (e.g., hearing loss and tinnitus induced by exposure to high levels of noise), chronic low-level noise exposure causes mental stress associated with known cardiovascular complications. According to recent estimates of the World Health Organization, exposure to traffic noise is responsible for a loss of more than 1.5 million healthy life years per year in Western Europe alone, a major part being related to annoyance, cognitive impairment, and sleep disturbance. Underlying mechanisms of noise-induced mental stress are centered on increased stress hormone levels, blood pressure, and heart rate, which in turn favor the development of cerebrocardiovascular disease such as stroke, arterial hypertension, ischemic heart disease, and myocardial infarction. Furthermore, traffic noise exposure is also associated with mental health symptoms and psychological disorders such as depression and anxiety, which further increase maladaptive coping mechanisms (e.g., alcohol and tobacco use). From a molecular point of view, experimental studies suggest that traffic noise exposure can increase stress hormone levels, thereby triggering inflammatory and oxidative stress pathways by activation of the nicotinamide adenine dinucleotide phosphate oxidase, uncoupling of endothelial/neuronal nitric oxide synthase inducing endothelial and neuronal dysfunction. This review elucidates the mechanisms underlying the relationship between noise exposure and cerebrocardiovascular and psychological disorders, focusing on mental stress signaling pathways including activation of the autonomous nervous system and endocrine signaling and its association with inflammation, oxidative stress, and vascular dysfunction.

19.
Br J Pharmacol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31833063

RESUMO

Risk factors in the environment such as air pollution and mental stress contribute to the development of chronic non-communicable disease. Air pollution was identified as the leading health risk factor in the physical environment, followed by water pollution, soil pollution/heavy metals/chemicals and occupational exposures, however neglecting the non-chemical environmental health risk factors (e.g. mental stress and noise). Epidemiological data suggest that environmental risk factors are associated with higher risk for cardiovascular, metabolic and mental diseases, including hypertension, heart failure, myocardial infarction, diabetes, arrhythmia, stroke, depression and anxiety disorders. We provide an overview on the impact of the external exposome comprising risk factors/exposures on cardiovascular health with a focus on dysregulation of stress hormones, mitochondrial function, redox balance and inflammation with special emphasis on the circadian clock. Finally, we assess the impact of circadian clock dysregulation on cardiovascular health and the potential of environment-specific preventive strategies or "chrono" therapy for cardioprotection.

20.
Oxid Med Cell Longev ; 2019: 5181429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781340

RESUMO

Objective: Atherogenic lipoproteins may impair vascular reactivity consecutively causing tissue damage in multiple organs via abnormal perfusion and excessive reactive oxygen species generation. We tested the hypothesis that chronic hypercholesterolemia causes endothelial dysfunction and cell loss in the retina. Methods: Twelve-month-old apolipoprotein E-deficient (ApoE-/-) mice and age-matched wild-type controls were used in this study (n = 8 per genotype for each experiment). Intraocular pressure, blood pressure, and ocular perfusion pressure were determined. Retinal arteriole responses were studied in vitro, and reactive oxygen and nitrogen species were quantified in the retinal and optic nerve cryosections. The expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the NADPH oxidase isoforms, NOX1, NOX2, and NOX4, were determined in retinal cryosections by immunofluorescence microscopy. Pro- and antioxidant redox genes were quantified in retinal explants by PCR. Moreover, cell number in the retinal ganglion cell layer and axon number in the optic nerve was calculated. Results: Responses to the endothelium-dependent vasodilator, acetylcholine, were markedly impaired in retinal arterioles of ApoE-/- mice (P < 0.01). LOX-1 (P = 0.0007) and NOX2 (P = 0.0027) expressions as well as levels of reactive oxygen species (P = 0.0022) were increased in blood vessels but not in other retinal structures. In contrast, reactive nitrogen species were barely detectable in both mouse genotypes. Messenger RNA for HIF-1α, VEGF-A, NOX1, and NOX2, but also for various antioxidant redox genes was elevated in the retina of ApoE-/- mice. Total cell number in the retinal ganglion cell layer did not differ between ApoE-/- and wild-type mice (P = 0.2171). Also, axon number in the optic nerve did not differ between ApoE-/- and wild-type mice (P = 0.6435). Conclusion: Apolipoprotein E deficiency induces oxidative stress and endothelial dysfunction in retinal arterioles, which may trigger hypoxia in the retinal tissue. Oxidative stress in nonvascular retinal tissue appears to be prevented by the upregulation of antioxidant redox enzymes, resulting in neuron preservation.

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