ABSTRACT
Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.
Subject(s)
DNA-Binding Proteins , Heart Failure , Mice , Animals , Humans , DNA-Binding Proteins/metabolism , Myocytes, Cardiac/metabolism , DNA Repair/genetics , DNA Damage/genetics , Heart Failure/genetics , EndonucleasesABSTRACT
To quantify the association between maternal uric acid levels and pre-eclampsia risk in a large collection of primigravid women. A case-control study (1365 cases of pre-eclampsia and 1886 normotensive controls) was conducted. Pre-eclampsia was defined as blood pressure ≥ 140/90 mmHg and proteinuria ≥ 300 mg/24 h. Sub-outcome analysis included early, intermediate, and late pre-eclampsia. Multivariable analysis for pre-eclampsia and its sub-outcomes was conducted using binary and multinomial logistic regression, respectively. Additionally, a systematic review and meta-analysis of cohort studies measuring uric acid levels < 20 weeks of gestation was performed to rule out reverse causation. There was a positive linear association between increasing uric acid levels and presence of pre-eclampsia. Adjusted odds ratio of pre-eclampsia was 1.21 (95%CI 1.11-1.33) for every one standard deviation increase in uric acid levels. No differences in the magnitude of association were observed between early and late pre-eclampsia. Three studies with uric acid measured < 20 weeks' gestation were identified, with a pooled OR for pre-eclampsia of 1.46 (95%CI 1.22-1.75) for a top vs. bottom quartile comparison. Maternal uric acid levels are associated with risk of pre-eclampsia. Mendelian randomisation studies would be helpful to further explore the causal role of uric acid in pre-eclampsia.
Subject(s)
Pre-Eclampsia , Pregnancy , Female , Humans , Prospective Studies , Uric Acid , Case-Control Studies , Blood Pressure/physiologyABSTRACT
Currently, traditional and non-traditional risk factors for cardiovascular disease have been established. The first group includes age, which constitutes one of the most important factors in the development of chronic diseases. The second group includes inflammation, the pathophysiology of which contributes to an accelerated process of vascular remodelling and atherogenesis in autoimmune diseases. Indeed, the term inflammaging has been used to refer to the inflammatory origin of ageing, explicitly due to the chronic inflammatory process associated with age (in healthy individuals). Taking this into account, it can be inferred that people with autoimmune diseases are likely to have an early acceleration of vascular ageing (vascular stiffness) as evidenced in the alteration of non-invasive cardiovascular tests such as pulse wave velocity. Thus, an association is created between autoimmunity and high morbidity and mortality rates caused by cardiovascular disease in this population group. The beneficial impact of the treatments for rheumatoid arthritis at the cardiovascular level has been reported, opening new opportunities for pharmacotherapy.
Subject(s)
Arthritis, Rheumatoid , Autoimmune Diseases , Cardiovascular Diseases , Arthritis, Rheumatoid/complications , Autoimmune Diseases/epidemiology , Autoimmunity , Cardiovascular Diseases/epidemiology , Humans , Pulse Wave AnalysisABSTRACT
Multiple small studies have suggested that women with pre-eclampsia present elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6). However, little is known regarding the source of this CRP and IL-6 increase. Therefore, the aim of this study was to evaluate the relationship between CRP and IL-6 levels with pre-eclampsia considering different confounding factors. Using data from a large Colombian case-control study (3,590 cases of pre-eclampsia and 4,564 normotensive controls), CRP and IL-6 levels were measured in 914 cases and 1297 controls. The association between maternal serum levels of CRP and IL-6 with pre-eclampsia risk was evaluated using adjusted logistic regression models. Pre-eclampsia was defined as presence of blood pressure ≥140/90 mmHg and proteinuria ≥300mg/24 h (or ≥1 + dipstick). There was no evidence of association between high levels of CRP and IL-6 with pre-eclampsia after adjusting for the following factors: maternal and gestational age, ethnicity, place and year of recruitment, multiple-pregnancy, socio-economic position, smoking, and presence of infections during pregnancy. The adjusted OR for 1SD increase in log-CRP and log-IL-6 was 0.96 (95%CI 0.85, 1.08) and 1.09 (95%CI 0.97, 1.22), respectively. Although previous reports have suggested an association between high CRP and IL-6 levels with pre-eclampsia, sample size may lack the sufficient power to draw robust conclusions, and this association is likely to be explained by unaccounted biases. Our results, the largest case-control study reported up to date, demonstrate that there is not a causal association between elevated levels of CRP and IL-6 and the presence of pre-eclampsia.
Subject(s)
C-Reactive Protein/metabolism , Interleukin-6/blood , Pre-Eclampsia/blood , Adolescent , Biomarkers/blood , Blood Pressure/physiology , Case-Control Studies , Female , Fetus , Gestational Age , Humans , Logistic Models , Pre-Eclampsia/diagnosis , Pregnancy , Young AdultABSTRACT
Chagas disease (CD) is one of the most important neglected tropical diseases in the American continent. Host-derived nitroxidative stress in response to Trypanosoma cruzi infection can induce tissue damage contributing to the progression of Chagas disease. Antioxidant supplementation has been suggested as adjuvant therapy to current treatment. In this article, we synthesize and discuss the current evidence regarding the use of antioxidants as adjunctive compounds to fight harmful reactive oxygen species and lower the tissue oxidative damage during progression of chronic Chagas disease. Several antioxidants evaluated in recent studies have shown potential benefits for the control of oxidative stress in the host's tissues. Melatonin, resveratrol, the combination of vitamin C/vitamin E (vitC/vitE) or curcumin/benznidazole, and mitochondria-targeted antioxidants seem to be beneficial in reducing plasma and cardiac levels of lipid peroxidation products. Nevertheless, further research is needed to validate beneficial effects of antioxidant therapies in Chagas disease.
Subject(s)
Antioxidants/therapeutic use , Chagas Disease/drug therapy , Animals , Antioxidants/pharmacology , Dogs , HumansABSTRACT
Pentraxin-3 has been reported as a promising biomarker of pre-eclampsia and its severity; however, available studies have small sample sizes, and analyses are not always adjusted for confounders. The aim of this study is to establish the strength of the association between maternal Pentraxin-3 level and pre-eclampsia or HELLP syndrome. It was a case-control study. Women with pre-eclampsia or HELLP syndrome were defined as cases, and women with healthy pregnancies at term (>37 weeks) were classified as controls. Plasma concentrations of Pentraxin-3 were determined at the time of delivery by quantitative enzyme immunoassay. Associations between Pentraxin-3 and pre-eclampsia and HELLP syndrome were assessed by multinomial logistic regression. Subsidiary analysis for the time of disease onset was also carried out. Odds ratios and 95% confidence intervals are reported. A total of 1024 pregnant women were included (461 controls, 368 pre-eclampsia, 195 HELLP). A positive log-linear relationship was found between the top pentraxin-3 quintile and HELLP syndrome. After adjustment for confounders (maternal age, ethnicity, socioeconomic position, date and place of recruitment, family history of pre-eclampsia, smoking, body mass index at beginning of pregnancy, gestational age and multiple pregnancy), the strength of the association was higher for HELLP syndrome [OR 1.13 (95% CI 1.08; 1.18)] than for pre-eclampsia [OR 1.03 (95% CI 1.03; 1.10)]. No difference according to time of onset or pentraxin-3 level was found. In summary, pentraxin-3 level was associated with pre-eclampsia, but it was more strongly associated with HELLP syndrome. Longitudinal studies with a lower probability of residual confounding are necessary to improve our knowledge about the role of pentraxin-3 in pre-eclampsia.
Subject(s)
C-Reactive Protein/metabolism , HELLP Syndrome/blood , Pre-Eclampsia/blood , Serum Amyloid P-Component/metabolism , Adolescent , Adult , Biomarkers/blood , Case-Control Studies , Female , Humans , Infant, Newborn , Male , Pregnancy , Young AdultABSTRACT
We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.
Subject(s)
Aging/genetics , Cellular Senescence/genetics , DNA Damage , DNA Repair , DNA-Binding Proteins/deficiency , Endonucleases/deficiency , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Age Factors , Aging/metabolism , Aging/pathology , Animals , Capillary Permeability , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA-Binding Proteins/genetics , Endonucleases/genetics , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/metabolism , Superoxides/metabolism , Vascular Stiffness , VasodilationABSTRACT
In recent years, gene therapy has been positioned as a real and safe option in the development of therapeutic alternatives for the cure and prevention of different diseases. It consists in the insertion of genetic material in a defective tissue or cell, through the use of a vector. There are several considerations for selecting the most appropriate vector, including the potential for binding and entry to the target cell, the ability of the genetic material to transfer to the nucleus, the ability to express the insert, and the absence of toxicity. In the current scenario, the most commonly used viral vectors are those derived from adeno-associated viruses (AAV). Characteristics such as biosafety, low toxicity and selective tropism have enabled its evaluation as a therapeutic option in many monogenic or complex diseases. Despite their advantages, AAV vectors have drawbacks, the most important being the patient's immune response to the vector, especially the response mediated by neutralizing antibodies (NAb). NAbs decrease the transduction of the vector and prevent the expression of the gene it transports, limiting its clinical application. Therefore, identifying and quantifying the presence and activity of NAbs is the first step in any gene therapy protocol with AAV vectors. The presence of NAbs depends mainly on exposure to the virus in nature and varies drastically according to age, geographic location and health status of the person evaluated.
En los últimos años la terapia génica se ha posicionado como una opción real y segura en el desarrollo de alternativas terapéuticas para la cura y la prevención de diferentes enfermedades. Consiste en la inserción de material genético en un tejido o célula defectuosa, mediante el uso de un vector. Existen varias consideraciones para seleccionar el vector más apropiado, incluyendo el potencial de unión y entrada a la célula diana, la capacidad de transferencia del material genético al núcleo, la habilidad de expresión del inserto y la ausencia de toxicidad. En el panorama actual, los vectores virales más utilizados son los derivados de los virus adenoasociados (AAV). Características como su bioseguridad, baja toxicidad y tropismo selectivo, han posibilitado su evaluación como opción terapéutica en un amplio número de enfermedades monogénicas o complejas. A pesar de sus ventajas, los vectores AAV presentan inconvenientes, siendo el más importante la respuesta inmune del paciente al vector, especialmente la respuesta mediada por anticuerpos neutralizantes (NAb). Los NAb disminuyen la transducción del vector e impiden la expresión del gen que transporta, limitando su aplicación clínica. Por lo tanto, identificar y cuantificar la presencia y actividad de los NAbs, es el primer paso en cualquier protocolo de terapia génica con vectores AAV. La presencia de NAb depende principalmente de la exposición al virus en la naturaleza y varía drásticamente según edad, localización geográfica y estado de salud de la persona evaluada.
Subject(s)
Dependovirus/genetics , Dependovirus/immunology , Genetic Therapy/methods , Parvoviridae Infections/genetics , Parvoviridae Infections/immunology , Antibodies, Neutralizing/analysis , Antibodies, Viral/analysis , Female , Genetic Vectors , Humans , Male , Parvoviridae Infections/virology , SerogroupABSTRACT
En los ó;ºltimos aó;±os la terapia gó;©nica se ha posicionado como una opció;n real y segura en el desarrollo de alternativas terapó;©uticas para la cura y la prevenció;n de diferentes enfermedades. Consiste en la inserció;n de material genó;©tico en un tejido o có;©lula defectuosa, mediante el uso de un vector. Existen varias consideraciones para seleccionar el vector más apropiado, incluyendo el potencial de unió;n y entrada a la có;©lula diana, la capacidad de transferencia del material genó;©tico al nó;ºcleo, la habilidad de expresió;n del inserto y la ausencia de toxicidad. En el panorama actual, los vectores virales más utilizados son los derivados de los virus adenoasociados (AAV). Características como su bioseguridad, baja toxicidad y tropismo selectivo, han posibilitado su evaluació;n como opció;n terapó;©utica en un amplio nó;ºmero de enfermedades monogó;©nicas o complejas. A pesar de sus ventajas, los vectores AAV presentan inconvenientes, siendo el más importante la respuesta inmune del paciente al vector, especialmente la respuesta mediada por anticuerpos neutralizantes (NAb). Los NAb disminuyen la transducció;n del vector e impiden la expresió;n del gen que transporta, limitando su aplicació;n clínica. Por lo tanto, identificar y cuantificar la presencia y actividad de los NAbs, es el primer paso en cualquier protocolo de terapia gó;©nica con vectores AAV. La presencia de NAb depende principalmente de la exposició;n al virus en la naturaleza y varía drásticamente segó;ºn edad, localizació;n geográfica y estado de salud de la persona evaluada.
In recent years, gene therapy has been positioned as a real and safe option in the development of therapeutic alternatives for the cure and prevention of different diseases. It consists in the insertion of genetic material in a defective tissue or cell, through the use of a vector. There are several considerations for selecting the most appropriate vector, including the potential for binding and entry to the target cell, the ability of the genetic material to transfer to the nucleus, the ability to express the insert, and the absence of toxicity. In the current scenario, the most commonly used viral vectors are those derived from adeno-associated viruses (AAV). Characteristics such as biosafety, low toxicity and selective tropism have enabled its evaluation as a therapeutic option in many monogenic or complex diseases. Despite their advantages, AAV vectors have drawbacks, the most important being the patientâs immune response to the vector, especially the response mediated by neutralizing antibodies (NAb). NAbs decrease the transduction of the vector and prevent the expression of the gene it transports, limiting its clinical application. Therefore, identifying and quantifying the presence and activity of NAbs is the first step in any gene therapy protocol with AAV vectors. The presence of NAbs depends mainly on exposure to the virus in nature and varies drastically according to age, geographic location and health status of the person evaluated.
Subject(s)
Humans , Male , Female , Genetic Therapy/methods , Dependovirus/genetics , Dependovirus/immunology , Parvoviridae Infections/genetics , Parvoviridae Infections/immunology , Parvoviridae Infections/virology , Antibodies, Neutralizing/analysis , Serogroup , Genetic Vectors , Antibodies, Viral/analysisABSTRACT
Infection with Trypanosoma cruzi Chagas, 1909 is reported to increase the production of reactive oxygen species in patients with Chagas disease. Mitochondria dysfunction, host inflammatory response and inadequate antioxidant response are described as the main factors leading to oxidative stress during acute and chronic stages of the disease. The Seahorse XFe24 extracellular flux platform allows energy metabolism determination through mitochondrial respiration and glycolysis measurements. XFe24 platform can be used in in vitro models of T. cruzi-infected cells, which allow the assessment and even modulation of endogenous conditions of infected cells, generating readouts of real-time cellular bioenergetics changes. In this protocol, we standardised the use of XFe24 technology in T. cruzi infected AC16 cardiomyocytes and SGHPL-5 trophoblasts. In addition, we provide a list of optimised assay specifications, advantages and critical steps to be considered during the process. Cardiomyocytes and trophoblasts are attractive target cells to evaluate the metabolic environment in acute, chronic and congenital Chagas transmission scenarios.
Subject(s)
Mitochondria/parasitology , Trypanosoma cruzi/physiology , Animals , Cell Line , Cell Respiration , Humans , Mice , Mitochondria/physiology , Myocytes, Cardiac/parasitology , Myocytes, Cardiac/physiology , Reactive Oxygen Species , Trophoblasts/parasitology , Trophoblasts/physiologyABSTRACT
Smoking exposure is associated with pregnancy complications, as are levels of folate, vitamin B12, and homocysteine. In nonpregnant adults, smoking exposure is associated negatively with folate and vitamin B12 levels and positively with homocysteine levels. A complete overview of the literature on this topic in pregnant women is lacking. To evaluate evidence of associations of maternal smoking exposure during pregnancy and levels of folate, homocysteine, and vitamin B12 in pregnancy and in cord blood, we searched MEDLINE, Embase, CINAHL, Cochrane, Scopus, Web of Science, and reference lists of relevant studies until August 2017. We selected studies in pregnant women describing the association of passive or active smoking and levels of folate, homocysteine, and/or vitamin B12. Data were extracted by two independent reviewers. We included 32 studies of 2,015 identified references with a total of 37,822 participants and more than 6,000 smokers. Twenty-eight studies measured folate, 14 measured vitamin B12, and 13 measured homocysteine. Nineteen out of 28 studies assessing folate reported significantly lower levels in pregnant women exposed to smoking compared with those unexposed. Vitamin B12 levels were lower in smoking mothers in eight out of 14 studies. Homocysteine levels tended to be higher in mothers exposed to smoking. Smoking exposure during pregnancy is generally associated with lower folate and vitamin B12 levels and higher homocysteine levels. This may help raise further awareness about the consequences of smoking and the need to encourage stopping smoking in all, especially in pregnant women.
Subject(s)
Folic Acid/blood , Homocysteine/blood , Maternal Exposure , Pregnancy Complications , Smoking , Vitamin B 12/blood , Female , Humans , Mothers , Pregnancy , Smoking CessationABSTRACT
Protein kinase G (PKG) Iα mediates the cyclic guanosine monophosphate-mediated vasodilatory effects induced by NO. Endothelium-derived hyperpolarizing factors (EDHFs), like H2O2 can activate PKGIα in a cyclic guanosine monophosphate-independent manner, but whether this is true for all EDHFs (e.g., S-nitrosothiols) is unknown. Here, we investigated the contribution of PKGIα to bradykinin-, H2O2-, L-S-nitrosocysteine-, and light-induced relaxation in porcine coronary arteries, making use of the fact that thioredoxin reductase inhibition with auranofin or 1-chloro-2,4-dinitrobenzene potentiates PKGIα. Thioredoxin reductase inhibition potentiated bradykinin and H2O2, but not L-S-nitrosocysteine or light. The relaxations by the latter 2 and bradykinin, but not those by H2O2, were prevented by the soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Yet, after S-nitrosothiol depletion with ethacrynic acid, thioredoxin reductase inhibition also potentiated light-induced relaxation, and this was prevented by the Na+-K+ ATPase inhibitor ouabain. This indicates that photorelaxation depends on sGC activation by S-nitrosothiols, while only after S-nitrosothiol depletion oxidized PKGIα comes into play, and acts via Na+-K+ ATPase. In conclusion, both bradykinin- and light-induced relaxation of porcine coronary arteries depend, at least partially, on oxidized PKGIα, and this does not involve sGC. H2O2 also acts via oxidized PKGIα in an sGC-independent manner. Yet, S-nitrosothiol-induced relaxation is PKGIα-independent. Clearly, PKG activation does not contribute universally to all EDHF responses, and targeting PKGIα may only mimick EDHF under certain conditions. It is therefore unlikely that PKGIα activators will be universal vasodilators.
Subject(s)
Biological Factors/metabolism , Cyclic GMP-Dependent Protein Kinase Type I/metabolism , S-Nitrosothiols/pharmacology , Animals , Enzyme Activation/drug effects , SwineABSTRACT
DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Δ/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/- mice. Ercc1Δ/- mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.
Subject(s)
Aging/metabolism , DNA Damage , Receptor, Angiotensin, Type 1/metabolism , Vascular Diseases/diet therapy , Aging/genetics , Angiotensin II/metabolism , Animals , Blood Pressure , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Diet , Endonucleases/genetics , Endonucleases/metabolism , Female , Humans , Male , Mice , Mice, Knockout , Nitric Oxide/metabolism , Receptor, Angiotensin, Type 1/genetics , Vascular Diseases/genetics , Vascular Diseases/metabolism , Vascular Diseases/physiopathology , VasodilationABSTRACT
Vascular aging plays a central role in health problems and mortality in older people. Apart from the impact of several classical cardiovascular risk factors on the vasculature, chronological aging remains the single most important determinant of cardiovascular problems. The causative mechanisms by which chronological aging mediates its impact, independently from classical risk factors, remain to be elucidated. In recent years evidence has accumulated that unrepaired DNA damage may play an important role. Observations in animal models and in humans indicate that under conditions during which DNA damage accumulates in an accelerated rate, functional decline of the vasculature takes place in a similar but more rapid or more exaggerated way than occurs in the absence of such conditions. Also epidemiological studies suggest a relationship between DNA maintenance and age-related cardiovascular disease. Accordingly, mouse models of defective DNA repair are means to study the mechanisms involved in biological aging of the vasculature. We here review the evidence of the role of DNA damage in vascular aging, and present mechanisms by which genomic instability interferes with regulation of the vascular tone. In addition, we present potential remedies against vascular aging induced by genomic instability. Central to this review is the role of diverse types of DNA damage (telomeric, non-telomeric and mitochondrial), of cellular changes (apoptosis, senescence, autophagy), mediators of senescence and cell growth (plasminogen activator inhibitor-1 (PAI-1), cyclin-dependent kinase inhibitors, senescence-associated secretory phenotype (SASP)/senescence-messaging secretome (SMS), insulin and insulin-like growth factor 1 (IGF-1) signaling), the adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-nuclear factor kappa B (NFκB) axis, reactive oxygen species (ROS) vs. endothelial nitric oxide synthase (eNOS)-cyclic guanosine monophosphate (cGMP) signaling, phosphodiesterase (PDE) 1 and 5, transcription factor NF-E2-related factor-2 (Nrf2), and diet restriction.
Subject(s)
Aging/genetics , Cardiovascular Diseases/genetics , DNA Damage , Animals , DNA Repair , Genomic Instability , HumansABSTRACT
Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; ß=0.28, P=2.47×10(-5)) and carotid intima-media thickness (cIMT; ß=-0.0061, P=2.89×10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy.
Subject(s)
Aging/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 1/metabolism , Muscle, Smooth, Vascular/enzymology , Myocytes, Smooth Muscle/enzymology , Vasodilation , Aging/genetics , Animals , Blood Pressure , Carotid Arteries/enzymology , Carotid Arteries/pathology , Carotid Artery Diseases/enzymology , Carotid Artery Diseases/genetics , Carotid Artery Diseases/pathology , Carotid Intima-Media Thickness , Cells, Cultured , Cellular Senescence , Cyclic GMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 1/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 1/genetics , Cyclic Nucleotide Phosphodiesterases, Type 5/genetics , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Dose-Response Relationship, Drug , Endonucleases/deficiency , Endonucleases/genetics , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Hydrolysis , Hyperplasia , Hypertension/enzymology , Hypertension/genetics , Hypertension/physiopathology , In Vitro Techniques , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Phenotype , Phosphodiesterase 5 Inhibitors/pharmacology , Polymorphism, Single Nucleotide , Second Messenger Systems , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
INTRODUCTION: Angiogenic factors, such as placental growth factor (PlGF) and soluble Flt-1 (sFlt-1), are key regulators of placental vascular development. Evidence from in vitro studies indicates that fatty acids can affect angiogenesis. We investigated the associations of maternal fish consumption and fatty acids levels with angiogenic factors during pregnancy, and in cord blood in a large population-based prospective cohort. METHODS: First trimester fish consumption was assessed among 3134 pregnant women using a food-frequency questionnaire. Plasma fatty acid levels were measured in second trimester. Plasma PlGF and sFlt-1 were measured in first and second trimester and in cord blood. Associations of fish consumption or fatty acid levels with angiogenic factors were assessed by multivariable linear regression analyses. RESULTS: There were no consistent associations of total fish or lean fish consumption with levels of PlGF, sFlt-1, or sFlt-1/PlGF ratio. Neither fatty fish nor shellfish were associated with angiogenic factors. Plasma omega-3 polyunsaturated fatty acids, which are the main type of fatty acids in fish, were inconsistently associated with angiogenic factors in second trimester and cord blood. Yet, higher levels of arachidonic acid, an omega-6 polyunsaturated fatty acid, were associated with lower levels of PlGF and sFlt-1. DISCUSSION: We found no consistent associations of fish consumption or fatty acids levels with angiogenic factors in a population with low fish consumption. Studies including populations with higher fish consumption are required to fully grasp the potential effects of maternal fish consumption on placental angiogenesis.