Publications by authors named "Anton J M Roks"

57 Publications

Vascular Ageing Features Caused by Selective DNA Damage in Smooth Muscle Cell.

Oxid Med Cell Longev 2021 31;2021:2308317. Epub 2021 Aug 31.

Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands.

Persistently unrepaired DNA damage has been identified as a causative factor for vascular ageing. We have previously shown that a defect in the function or expression of the DNA repair endonuclease ERCC1 (excision repair cross complement 1) in mice leads to accelerated, nonatherosclerotic ageing of the vascular system from as early as 8 weeks after birth. Removal of ERCC1 from endothelial alone partly explains this ageing, as shown in endothelial-specific knockout mice. In this study, we determined vascular ageing due to DNA damage in vascular smooth muscle cells, as achieved by smooth muscle-selective genetic removal of ERCC1 DNA repair in mice (SMC-KO: SM22Cre+ fl/-). Vascular ageing features in SMC-KO and their wild-type littermates (WT: SM22Cre+ fl/+) were examined at the age of 14 weeks and 25 weeks. Both SMC-KO and WT mice were normotensive. Compared to WT, SMC-KO showed a reduced heart rate, fractional shortening, and cardiac output. SMC-KO showed progressive features of nonatherosclerotic vascular ageing as they aged from 14 to 25 weeks. Decreased subcutaneous microvascular dilatation and increased carotid artery stiffness were observed. Vasodilator responses measured in aortic rings in organ baths showed decreased endothelium-dependent and endothelium-independent responses, mostly due to decreased NO-cGMP signaling. NADPH oxidase 2 and phosphodiesterase 1 inhibition improved dilations. SMC-KO mice showed elevated levels of various cytokines that indicate a balance shift in pro- and anti-inflammatory pathways. In conclusion, SMC-KO mice showed a progressive vascular ageing phenotype in resistant and conduit arteries that is associated with cardiac remodeling and contractile dysfunction. The changes induced by DNA damage might be limited to VSMC but eventually affect EC-mediated responses. The fact that NADPH oxidase 2 as wells as phosphodiesterase 1 inhibition restores vasodilation suggests that both decreased NO bioavailability and cGMP degradation play a role in local vascular smooth muscle cell ageing induced by DNA damage.
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http://dx.doi.org/10.1155/2021/2308317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423575PMC
August 2021

Selective Phosphodiesterase 1 Inhibition Ameliorates Vascular Function, Reduces Inflammatory Response, and Lowers Blood Pressure in Aging Animals.

J Pharmacol Exp Ther 2021 Aug 7;378(2):173-183. Epub 2021 Jun 7.

Dept. of Internal Medicine (K.G., E.A.A., E.R.-B., I.M.V.d.B.-G., A.M., R.d.V., A.H.J.D., A.J.M.R.), Dept. of Molecular Genetics (I.v.d.P., R.B.), Dept. of Vascular Surgery (I.v.d.P.), Erasmus Medical Center, Rotterdam, The Netherlands, and Intra-Cellular Therapies, Inc., New York, New York (S.D., W.Y., G.L.S., R.E.D.)

Diminished nitric oxide-cGMP-mediated relaxation plays a crucial role in cardiovascular aging, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately, cardiovascular dysfunction. Aging is the time-related worsening of physiologic function due to complex cellular and molecular interactions, and it is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice provides us an efficient tool to accelerate vascular aging, explore mechanisms, and test potential treatments. Previously, we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular aging. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular aging features in mice. Compared with wild-type mice, mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in mice. An 8-week treatment with 100 mg/kg per day ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in mice. These findings suggest phosphodiesterase 1 inhibition would provide a powerful tool for nitric oxide-cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to aging. SIGNIFICANCE STATEMENT: The findings implicate the key role of phosphodiesterase 1 in vascular function and might be of clinical importance for the prevention of mortalities and morbidities related to vascular complications during aging, as well as for patients with progeria that show a high risk of cardiovascular disease.
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http://dx.doi.org/10.1124/jpet.121.000628DOI Listing
August 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Notch-Rho-cGMP interaction: common point of convergence in microvascular aging-related disease.

Clin Sci (Lond) 2021 May;135(10):1209-1212

British Heart Foundation Centre of Research Excellence, King's College London, School of Cardiovascular Medicine and Science, London, United Kingdom.

Vascular smooth muscle biology is increasingly exploited as an interventional target in vascular disease. Vascular smooth muscle Notch3-Rho kinase-cGMP interaction has been implicated in brain and peripheral arteriopathy in CADASIL. In the present commentary, we discuss the potential implications for other, more common non-atherosclerotic microvascular diseases: INOCA and HFpEF. The relation to mechanotransduction, to cellular senescence and to sGC activators as potential intervention agents are described.
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http://dx.doi.org/10.1042/CS20210288DOI Listing
May 2021

Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice.

Aging Cell 2021 02 23;20(2):e13302. Epub 2021 Jan 23.

Centre for Health Protection, National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands.

Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1 mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair-deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.
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http://dx.doi.org/10.1111/acel.13302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884048PMC
February 2021

Inflammaging as a link between autoimmunity and cardiovascular disease: the case of rheumatoid arthritis.

RMD Open 2021 01;7(1)

Research Division, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Cundinamarca, Colombia.

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.
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http://dx.doi.org/10.1136/rmdopen-2020-001470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817822PMC
January 2021

Nitric Oxide-cGMP Signaling in Hypertension: Current and Future Options for Pharmacotherapy.

Hypertension 2020 10 24;76(4):1055-1068. Epub 2020 Aug 24.

From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands (E.A.A., K.G., A.J., A.H.J.D., A.J.M.R.).

For the treatment of systemic hypertension, pharmacological intervention in nitric oxide-cyclic guanosine monophosphate signaling is a well-explored but unexploited option. In this review, we present the identified drug targets, including oxidases, mitochondria, soluble guanylyl cyclase, phosphodiesterase 1 and 5, and protein kinase G, important compounds that modulate them, and the current status of (pre)clinical development. The mode of action of these compounds is discussed, and based upon this, the clinical opportunities. We conclude that drugs that directly target the enzymes of the nitric oxide-cyclic guanosine monophosphate cascade are currently the most promising compounds, but that none of these compounds is under investigation as a treatment option for systemic hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15856DOI Listing
October 2020

Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.

Clin Sci (Lond) 2020 04;134(7):727-746

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1042/CS20190124DOI Listing
April 2020

The importance of the nitric oxide-cGMP pathway in age-related cardiovascular disease: Focus on phosphodiesterase-1 and soluble guanylate cyclase.

Basic Clin Pharmacol Toxicol 2020 Aug 3;127(2):67-80. Epub 2019 Oct 3.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Among ageing-related illnesses, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality causing one-third of all deaths worldwide. Ageing evokes a number of functional, pharmacological and morphological changes in the vasculature, accompanied by a progressive failure of protective and homeostatic mechanisms, resulting in target organ damage. Impaired vasomotor, proliferation, migration, antithrombotic and anti-inflammatory function in both the endothelial and vascular smooth muscle cells are parts of the vascular ageing phenotype. The endothelium regulates these functions by the release of a wide variety of active molecules including endothelium-derived relaxing factors such as nitric oxide, prostacyclin (PGI ) and endothelium-derived hyperpolarization (EDH). During ageing, a functional decay of the nitric oxide pathway takes place. Nitric oxide signals to VSMC and other important cell types for vascular homeostasis through the second messenger cyclic guanosine monophosphate (cGMP). Maintenance of proper cGMP levels is an important goal in sustainment of proper vascular function during ageing. For this purpose, different components can be targeted in this signalling system, and among them, phosphodiesterase-1 (PDE1) and soluble guanylate cyclase (sGC) are crucial. This review focuses on the role of PDE1 and sGC in conditions that are relevant for vascular ageing.
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http://dx.doi.org/10.1111/bcpt.13319DOI Listing
August 2020

Correction to: The role of DNA methylation and histone modifications in blood pressure: a systematic review.

J Hum Hypertens 2020 Feb;34(2):193

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41371-019-0234-7DOI Listing
February 2020

The role of DNA methylation and histone modifications in blood pressure: a systematic review.

J Hum Hypertens 2019 10 25;33(10):703-715. Epub 2019 Jul 25.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.

Epigenetic mechanisms might play a role in the pathophysiology of hypertension, a major risk factor for cardiovascular disease and renal failure. We aimed to systematically review studies investigating the association between epigenetic marks (global, candidate-gene or genome-wide methylation of DNA, and histone modifications) and blood pressure or hypertension. Five bibliographic databases were searched until the 7th of December 2018. Of 2984 identified references, 26 articles based on 25 unique studies met our inclusion criteria, which involved a total of 28,382 participants. The five studies that assessed global DNA methylation generally found lower methylation levels with higher systolic blood pressure, diastolic blood pressure, and/or presence of hypertension. Eighteen candidate-gene studies reported, in total, 16 differentially methylated genes, including renin-angiotensin-system-related genes (ACE promoter and AGTR1) and genes involved in sodium homeostasis and extracellular fluid volume maintenance system (NET promoter, SCNN1A, and ADD1). Between the three identified epigenome-wide association studies (EWAS), lower methylation levels of SULF1, EHMT2, and SKOR2 were found in hypertensive patients as compared with normotensive subjects, and lower methylation levels of PHGDH, SLC7A11, and TSPAN2 were associated with higher systolic and diastolic blood pressure. In summary, the most convincing evidence has been reported from candidate-gene studies, which show reproducible epigenetic changes in the interconnected renin-angiotensin and inflammatory systems. Our study highlights gaps in the literature on the role of histone modifications in blood pressure and the need to conduct high-quality studies, in particular, hypothesis-generating studies that may help to elucidate new molecular mechanisms.
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http://dx.doi.org/10.1038/s41371-019-0218-7DOI Listing
October 2019

Phytoestrogen supplementation and body composition in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials.

Maturitas 2018 Sep 22;115:74-83. Epub 2018 Jun 22.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Almedicus, Tirana, Albania.

Phytoestrogen-based medications are commonly used by menopausal women, and especially by obese postmenopausal women, to relieve menopausal symptoms. Substitution of animal with soy protein is often used in weight loss regimens, yet the effect of phytoestrogens, the main constituent of soy foods, on body composition is not completely understood. We conducted a systematic review and meta-analysis to investigate the associations between phytoestrogen supplementation and body weight and the main parameters of body composition in postmenopausal women. A literature search was done using 5 electronic databases from inception to April 2018. Randomized controlled trials (RCTs) with postmenopausal women comparing phytoestrogen supplementation followed by usual diet and placebo were included in the present meta-analysis. From 5932 references, we identified 23 RCTs that met our inclusion criteria, with a total of 1880 postmenopausal women. No association was observed between phytoestrogen supplementation and body weight, body mass index, waist and hip circumference, total fat mass or percentage of body fat. However, the use of phytoestrogens supplementation was associated with a slight decrease in waist-hip ratio; the pooled mean difference was -0.01 cm (95%CI: -0.01 to -0.006). In subgroup analysis, we found a modest decrease in body weight with phytoestrogens supplementation compared with placebo in healthy postmenopausal women [pooled mean difference of changes -0.28 kg (95%CI: -0.52 to -0.04)] and in RCTs with a median number of participants of 66 or less [pooled mean difference of changes -0.49 kg (95%CI: -0.87 to -0.11)]. In contrast, phytoestrogen supplementation was associated with increased body weight in postmenopausal women with preexisting metabolic disorders (prediabetes, type 2 diabetes, prehypertension and hyperlipidemia) [pooled mean difference of changes: 0.78 kg (95%CI: 0.53-1.03)]. In addition, there were some indications that some types of phytoestrogens, such as daidzein, but not soy products or isoflavone mix, could lead to modest adverse changes in body composition in menopausal women. Therefore, future studies should investigate the potential adverse effects of phytoestrogen supplementation on body composition among postmenopausal women.
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http://dx.doi.org/10.1016/j.maturitas.2018.06.012DOI Listing
September 2018

Endothelium-derived hyperpolarizing factor and protein kinase G Iα activation: HO versus S-nitrosothiols.

Eur J Pharmacol 2018 May 14;827:112-116. Epub 2018 Mar 14.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address:

Protein kinase G (PKG) Iα mediates the cyclic guanosine monophosphate-mediated vasodilatory effects induced by NO. Endothelium-derived hyperpolarizing factors (EDHFs), like HO 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-, HO-, 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 HO, but not L-S-nitrosocysteine or light. The relaxations by the latter 2 and bradykinin, but not those by HO, 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. HO 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.
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http://dx.doi.org/10.1016/j.ejphar.2018.03.019DOI Listing
May 2018

Development of PKG Iα (Protein Kinase G Iα)-Dimerizing Antihypertensive Drugs: Are We Standing at the Shore of the Rubicon?

Hypertension 2017 09 17;70(3):490-492. Epub 2017 Jul 17.

From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09723DOI Listing
September 2017

Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging mice.

Clin Sci (Lond) 2017 Aug 13;131(15):1941-1953. Epub 2017 Jul 13.

Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands

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 ( 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). mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser-eNOS were compromised in 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 mice. 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.
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http://dx.doi.org/10.1042/CS20170026DOI Listing
August 2017

Impact of early- and late-onset preeclampsia on features of placental and newborn vascular health.

Placenta 2017 01 27;49:72-79. Epub 2016 Nov 27.

Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre Rotterdam, Postbus 2040, 3000 CA Rotterdam, The Netherlands. Electronic address:

Introduction: Offspring exposed to preeclampsia (PE) show an increased risk of cardiovascular disease in adulthood. We hypothesize that this is mediated by a disturbed vascular development of the placenta, umbilical cord and fetus. Therefore, we investigated associations between early-onset PE (EOPE), late-onset PE (LOPE) and features of placental and newborn vascular health.

Methods: We performed a nested case-control study in The Rotterdam Periconceptional Cohort, including 30 PE pregnancies (15 EOPE, 15 LOPE) and 218 control pregnancies (164 uncomplicated controls, 54 complicated controls including 28 fetal growth restriction, 26 preterm birth) and assessed macroscopic and histomorphometric outcomes of the placenta and umbilical cord.

Results: A significant association was observed between PE and a smaller umbilical vein area and wall thickness, independent of gestational age and birth weight. In EOPE we observed significant associations with a lower weight, length and width of the placenta, length of the umbilical cord, and thickness and wall area of the umbilical vein and artery. These associations attenuated after gestational age and birth weight adjustment. In LOPE a significant association with a larger placental width and smaller umbilical vein wall thickness was shown, independent of gestational age and birth weight.

Discussion: Our study suggests that PE is associated with a smaller umbilical cord vein area and wall thickness, independent of gestational age and birth weight, which may serve as a proxy of disturbed cardiovascular development in the newborn. Follow-up studies are needed to ultimately predict and lower the risk of cardiovascular disease in offspring exposed to PE.
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http://dx.doi.org/10.1016/j.placenta.2016.11.014DOI Listing
January 2017

DNA Damage: A Main Determinant of Vascular Aging.

Int J Mol Sci 2016 May 18;17(5). Epub 2016 May 18.

Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands.

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.
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http://dx.doi.org/10.3390/ijms17050748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881569PMC
May 2016

Phosphodiesterase 1 regulation is a key mechanism in vascular aging.

Clin Sci (Lond) 2015 Dec 25;129(12):1061-75. Epub 2015 Jun 25.

Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands

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; β=0.28, P=2.47×10(-5)) and carotid intima-media thickness (cIMT; β=-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.
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http://dx.doi.org/10.1042/CS20140753DOI Listing
December 2015

Angiotensin II type 2 receptor- and acetylcholine-mediated relaxation: essential contribution of female sex hormones and chromosomes.

Hypertension 2015 Aug 8;66(2):396-402. Epub 2015 Jun 8.

From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.

Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium-derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y(-)) from the Y chromosome, allowing XY(-) mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY(-)Sry and XXSry transgenic mice develop into gonadal male mice. Four-core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY(-)Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY(-) female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R-dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05303DOI Listing
August 2015

Hypertension: renin-angiotensin-aldosterone system alterations.

Circ Res 2015 Mar;116(6):960-75

From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.303587DOI Listing
March 2015

Effect of a stable Angiotensin-(1-7) analogue on progenitor cell recruitment and cardiovascular function post myocardial infarction.

J Am Heart Assoc 2015 Feb 5;4(2). Epub 2015 Feb 5.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands (B.S.P., R.V.V., R.D.V., J.D., A.M.R.).

Background: Angiotensin-(1-7) improves cardiac function and remodeling after myocardial infarction (MI). This may involve recruitment of hematopoietic progenitor cells that support angiogenesis. However, angiotensin-(1-7) is rapidly metabolized in plasma and tissue. The authors investigated in mice the effect of a metabolically stable angiotensin-(1-7) analogue, cyclic angiotensin-(1-7), on progenitor cell recruitment and on the heart post MI, when given in the angiogenesis phase of remodeling.

Methods And Results: Angiogenic progenitor cell recruitment was measured by using flow cytometry 24 and 72 hours after a daily bolus injection of cyclic angiotensin-(1-7) in healthy C57BL/6 mice. Further, mice underwent MI or sham surgery and subsequently received saline or 2 different doses of cyclic angiotensin-(1-7) for 3 or 9 weeks. Cyclic angiotensin-(1-7) increased circulating hematopoietic progenitor cells at 24 hours but not 72 hours. Post MI, cyclic angiotensin-(1-7) diminished cardiomyocyte hypertrophy and reduced myogenic tone, without altering cardiovascular function or cardiac histology at 9 weeks. Importantly, cyclic angiotensin-(1-7)-treated mice had reduced cardiac capillary density at 3 weeks after MI but not after 9 weeks. Finally, cyclic angiotensin-(1-7) decreased tube formation by cultured human umbilical vein endothelial cells.

Conclusions: Our results suggest that cyclic angiotensin-(1-7), when given early after MI, recruits progenitor cells but does not lead to improved angiogenesis, most likely because it simultaneously exerts antiangiogenic effect in adult endothelial cells. Apparently, optimal treatment with cyclic angiotensin-(1-7) depends on the time point of onset of application after MI.
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http://dx.doi.org/10.1161/JAHA.114.001510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345874PMC
February 2015

Angiotensin II, oxidative stress and stem cell therapy: a matter of delicacy.

Authors:
Anton J M Roks

Clin Sci (Lond) 2015 Jun;128(11):749-50

*Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.

Optimization of stem cell therapy after cardiovascular and renal injury depends on many factors, among which is stem cell donor health. The renin-angiotensin system (RAS) plays an important role in cardiovascular and renal homoeostasis and pathophysiology. It is becoming increasingly clear that the RAS affects the therapeutic performance of stem cells. In this issue of Clinical Science, Kankuri et al. dig deeper into the consequences of excessive angiotensin II signalling and reactive oxygen species (ROS) formation in the stem cell donor, applying a model of regenerative medicine after renal injury.
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http://dx.doi.org/10.1042/CS20150082DOI Listing
June 2015

Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats.

Am J Physiol Lung Cell Mol Physiol 2014 Aug 20;307(3):L261-72. Epub 2014 Jun 20.

Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg·kg(-1)·day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 μg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg·kg(-1)·day(-1)) in two models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2-3 and PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.
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http://dx.doi.org/10.1152/ajplung.00345.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121644PMC
August 2014

Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: implications for the ACE-inhibitor-induced effects in patients with coronary artery disease.

Clin Sci (Lond) 2014 Mar;126(6):441-9

*Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.

The efficacy of the ACE (angiotensin-converting enzyme) inhibitor perindopril in coronary artery disease [EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery disease) study] is associated with the rs12050217 A/G single nucleotide polymorphism in the B1 receptor (bradykinin type 1 receptor) gene. To investigate the underlying mechanism, we examined the effect of this polymorphism on B1-receptor-mediated coronary artery dilation and peripheral blood mononuclear cell activation. Vasorelaxant responses of human coronary microarteries from subjects without coronary disease to des-Arg(9)-bradykinin and to bradykinin were studied in organ bath experiments. Des-Arg9-bradykinin responses were endothelium-dependent and exclusively mediated by B1 receptors, whereas responses to bradykinin were induced through B2 receptors (bradykinin type 2 receptors). The presence of the G allele reduced the response to 3 × 10(-8) mol/l des-Arg(9)-bradykinin by 29% [AA (n=13) compared with AG/GG (n=8); P<0.03], and tended to lower concentration-related responses (P=0.065) to this agonist, whereas the responses to bradykinin were unaffected by the rs12050217 genotype. In freshly obtained human mononuclear cells 1 μmol/l des-Arg(9)-bradykinin increased expression of the pro-inflammatory factors CXCL5 (CXC chemokine ligand 5) and IL6 (interleukin-6). These responses were not affected by genotype and exclusively occurred in blood cells from women, correlating (in the case of CXCL5) with their plasma 17β-oestradiol levels (r(2)=0.32, P=0.02; n=17). IL-1β (interleukin-1β) increased CXCL5 and IL6 expression in both genders, and this response was not associated with 17β-oestradiol levels. The gender difference in responses to B1 receptor stimulation in blood mononuclear cells implies possible gender differences in the response to ACE inhibitor therapy, which needs to be studied more comprehensively. The observed decrease in coronary vasodilator response might contribute to the impaired treatment response to perindopril of G allele carriers found in the EUROPA study.
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http://dx.doi.org/10.1042/CS20130204DOI Listing
March 2014

Genomic instability and vascular aging: a focus on nucleotide excision repair.

Trends Cardiovasc Med 2014 Feb 15;24(2):61-8. Epub 2013 Aug 15.

Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands. Electronic address:

Genomic instability is recognized as one of the primary mechanisms that lead to organismal aging. When genomic maintenance systems, such as nucleotide excision repair, are defective, genomic instability is promoted, which causes accelerated aging (progeria). This can be observed in humans as well as in mouse models of progeroid syndromes. The role of genomic instability related to nuclear DNA is currently under investigation with respect to its role in cardiovascular disease, and in particular those cardiovascular diseases that are associated with vascular aging. In this review, we highlight the first findings in this field of research that come from experiments in nucleotide excision repair-defective mouse models and from genetic studies. Possible mechanisms that mediate the consequences of genomic instability at the local vascular and at the systemic level, such as cell senescence, mutations, mitochondrial damage, and sirtuin 1 and IGF-1 decrease, are discussed and important goals for future research are set.
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http://dx.doi.org/10.1016/j.tcm.2013.06.005DOI Listing
February 2014

Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury.

Am J Physiol Lung Cell Mol Physiol 2013 Sep 28;305(5):L341-51. Epub 2013 Jun 28.

Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, the Netherlands.

Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 μg·kg(-1)·day(-1)] and AT2 [dKcAng-(1-7); 5-20 μg·kg(-1)·day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester (25 mg·kg(-1)·day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.
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http://dx.doi.org/10.1152/ajplung.00360.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763032PMC
September 2013

Key developments in renin-angiotensin-aldosterone system inhibition.

Nat Rev Nephrol 2013 Jan 20;9(1):26-36. Epub 2012 Nov 20.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.

The renin-angiotensin-aldosterone system (RAAS) was initially thought to be fairly simple. However, this idea has been challenged following the development of RAAS blockers, including renin inhibitors, angiotensin-converting-enzyme (ACE) inhibitors, type 1 angiotensin II (AT(1))-receptor blockers and mineralocorticoid-receptor antagonists. Consequently, new RAAS components and pathways that might contribute to the effectiveness of these drugs and/or their adverse effects have been identified. For example, an increase in renin levels during RAAS blockade might result in harmful effects via stimulation of the prorenin receptor (PRR), and prorenin-the inactive precursor of renin-might gain enzymatic activity on PRR binding. The increase in angiotensin II levels that occurs during AT(1)-receptor blockade might result in beneficial effects via stimulation of type 2 angiotensin II receptors. Moreover, angiotensin 1-7 levels increase during ACE inhibition and AT(1)-receptor blockade, resulting in Mas receptor activation and the induction of cardioprotective and renoprotective effects, including stimulation of tissue repair by stem cells. Finally, a role of angiotensin II in sodium and potassium handling in the distal nephron has been identified. This finding is likely to have important implications for understanding the effects of RAAS inhibition on whole body sodium and potassium balance.
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http://dx.doi.org/10.1038/nrneph.2012.249DOI Listing
January 2013

Compound 21 induces vasorelaxation via an endothelium- and angiotensin II type 2 receptor-independent mechanism.

Hypertension 2012 Sep 16;60(3):722-9. Epub 2012 Jul 16.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Angiotensin II type 2 (AT(2)) receptor stimulation has been linked to vasodilation. Yet, AT(2) receptor-independent hypertension and hypotension (or no effect on blood pressure) have been observed in vivo after application of the AT(2) receptor agonist compound 21 (C21). We, therefore, studied its effects in vitro, using preparations known to display AT(2) receptor-mediated responses. Hearts of Wistar rats, spontaneously hypertensive rats (SHRs), C57Bl/6 mice, and AT(2) receptor knockout mice were perfused according to Langendorff. Mesenteric and iliac arteries of these animals, as well as coronary microarteries from human donor hearts, were mounted in Mulvany myographs. In the coronary vascular bed of Wistar rats, C57Bl/6 mice, and AT(2) receptor knockout mice, C21 induced constriction followed by dilation. SHR hearts displayed enhanced constriction and no dilation. Irbesartan (angiotensin II type 1 receptor blocker) abolished the constriction and enhanced or (in SHRs) reintroduced dilation, and PD123319 (AT(2) receptor blocker) did not block the latter. C21 relaxed preconstricted vessels of all species, and this did not depend on angiotensin II receptors, the endothelium, or the NO-guanylyl cyclase-cGMP pathway. C21 constricted SHR iliac arteries but none of the other vessels, and irbesartan prevented this. C21 shifted the concentration-response curves to U46619 (thromboxane A(2) analog) and phenylephrine (α-adrenoceptor agonist) but not ionomycine (calcium ionophore) to the right. In conclusion, C21 did not cause AT(2) receptor-mediated vasodilation. Yet, it did induce vasodilation by blocking calcium transport into the cell and constriction via angiotensin II type 1 receptor stimulation. The latter effect is enhanced in SHRs. These data may explain the varying effects of C21 on blood pressure in vivo.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.196022DOI Listing
September 2012

Nucleotide excision DNA repair is associated with age-related vascular dysfunction.

Circulation 2012 Jul 15;126(4):468-78. Epub 2012 Jun 15.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands.

Background: Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction.

Methods And Results: In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity.

Conclusions: Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.104380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430727PMC
July 2012

Red wine extract protects against oxidative-stress-induced endothelial senescence.

Clin Sci (Lond) 2012 Oct;123(8):499-507

Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center, Dr Molewaterplein 50-60, 3015 GE, Rotterdam, The Netherlands.

Red wine polyphenols may preserve endothelial function during aging. Endothelial cell senescence enhances age-related endothelial dysfunction. We investigated whether RWE (red wine extract) prevents oxidative-stress-induced senescence in HUVECs (human umbilical-vein endothelial cells). Senescence was induced by exposing HUVECs to tBHP (t-butylhydroperoxide), and quantified by senescence-associated β-galactosidase staining. RWE (0-50 μg/ml) concentration dependently decreased senescence by maximally 33±7.1%. RWE prevented the senescence-associated increase in p21 protein expression, inhibited tBHP-induced DNA damage of endothelial cells and induced relaxation of PCAs (porcine coronary arteries). Inhibition of SIRT1 (sirtuin 1) by sirtinol partially reversed the effect of RWE on tBHP-induced senescence, whereas both the NOS (nitric oxide synthase) inhibitor L-NMMA (NG-monomethyl-L-arginine) and the COX (cyclo-oxygenase) inhibitor indomethacin fully inhibited it. Furthermore, incubation of HUVECs with RWE increased eNOS (endothelial NOS) and COX-2 mRNA levels as well as phosphorylation of eNOS at Ser1177. RWE protects endothelial cells from tBHP-induced senescence. NO and COX-2, in addition to activation of SIRT1, play a critical role in the inhibition of senescence induction in human endothelial cells by RWE.
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http://dx.doi.org/10.1042/CS20110679DOI Listing
October 2012
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