Publications by authors named "Ingrid van der Pluijm"

38 Publications

Selective PDE1 inhibition ameliorates vascular function, reduces inflammatory response, and lowers blood pressure in ageing animals.

J Pharmacol Exp Ther 2021 Jun 7. Epub 2021 Jun 7.

Erasmus MC, Netherlands

Diminished nitric oxide - cGMP -mediated relaxation plays a crucial role in cardiovascular ageing, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately cardiovascular dysfunction. Ageing is the time-related worsening of physiological function due to complex cellular and molecular interactions, and 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 ageing, explore mechanisms, and test potential treatments. Previously we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular ageing. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular ageing features in mice. Compared to 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/d 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 PDE1 inhibition would provide a powerful tool for nitric oxide - cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to ageing. The findings implicate the key role of PDE1 in vascular function and might be of clinical importance for prevention of mortalities and morbidities related to vascular complications during ageing, as well as for progeria patients that show a high risk of cardiovascular disease.
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http://dx.doi.org/10.1124/jpet.121.000628DOI Listing
June 2021

Abnormal Aortic Wall Properties in Women with Turner Syndrome.

Aorta (Stamford) 2020 Oct 23;8(5):121-131. Epub 2020 Dec 23.

Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background:  Turner syndrome (TS) is associated with aortic dilatation and dissection, but the underlying process is unclear. The aim of this study was to investigate the elastic properties and composition of the aortic wall in women with TS.

Methods:  In this cross-sectional study, 52 women with TS aged 35 ± 13 years (50% monosomy, 12 with bicuspid aortic valve [BAV] and 4 with coarctation) were investigated using carotid-femoral pulse wave velocity (CF-PWV) by echocardiography and ascending aortic distensibility (AAD) and aortic arch pulse wave velocity (AA-PWV) by magnetic resonance imaging (MRI). As control group, 13 women with BAV without TS and 48 healthy patients were included.

Results:  Women with TS showed a higher AA-PWV (β = 1.08, confidence interval [CI]: 0.54-1.62) after correcting for age and comorbidities compared with controls. We found no significant difference in AAD and CF-PWV. In women with TS, the presence of BAV, coarctation of the aorta, or monosomy (45, X) was not associated with aortic stiffness. In addition, aortic tissue samples were investigated with routine and immunohistochemical stains in five additional women with TS who were operated. The tissue showed more compact smooth muscle cell layers with abnormal deposition and structure of elastin and diminished or absent expression of contractile proteins desmin, actin, and caldesmon, as well as the progesterone receptor.

Conclusion:  Both aortic arch stiffness measurements on MRI and histomorphological changes point toward an inherent abnormal thoracic aortic wall in women with TS.
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http://dx.doi.org/10.1055/s-0040-1714384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758113PMC
October 2020

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment.

Cardiovasc Drugs Ther 2020 Dec 7. Epub 2020 Dec 7.

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

Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.
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http://dx.doi.org/10.1007/s10557-020-07116-4DOI Listing
December 2020

Pre-Operative Fasting Provides Long Term Protection Against Chronic Renal Damage Induced by Ischaemia Reperfusion Injury in Wild Type and Aneurysm Prone Fibulin-4 Mice.

Eur J Vasc Endovasc Surg 2020 Dec 5;60(6):905-915. Epub 2020 Oct 5.

Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Objective: Renal ischaemia reperfusion injury (IRI) is inevitable during open repair of pararenal aortic aneurysms. Pre-operative fasting potently increases resistance against IRI. The effect of fasting on IRI was examined in a hypomorphic Fibulin-4 mouse model (Fibulin-4), which is predisposed to develop aortic aneurysms.

Methods: Wild type (WT) and Fibulin-4 mice were either fed ad libitum (AL) or fasted for two days before renal IRI induction by temporary clamping of the renal artery and vein of both kidneys. Six hours, 48 h, and seven days post-operatively, serum urea levels, renal histology, and mRNA expression levels of inflammatory and injury genes were determined to assess kidney function and damage. Additionally, matrix metalloproteinase activity in the kidney was assessed six months after IRI.

Results: Two days of fasting improved survival the first week after renal IRI in WT mice compared with AL fed mice. Short term AL fed Fibulin-4 mice showed improved survival and kidney function compared with AL fed WT mice, which could not be further enhanced by fasting. Both fasted WT and Fibulin-4 mice showed improved survival, kidney function and morphology compared with AL fed mice six months after renal IRI. Fibulin-4 kidneys of fasted mice showed reduced apoptosis together with increased matrix metalloprotease activity levels compared with AL fed Fibulin-4 mice, indicative of increased matrix remodelling.

Conclusion: Fibulin-4 mice are naturally protected against the short-term, but not long-term, consequences of renal IRI. Pre-operative fasting protects against renal IRI and prevents (long-term) deterioration of kidney function and morphology in both WT and Fibulin-4 mice. These data suggest that pre-operative fasting may decrease renal damage in patients undergoing open abdominal aneurysm repair.
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http://dx.doi.org/10.1016/j.ejvs.2020.08.013DOI Listing
December 2020

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands.

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of mice, can be used as a tool to accelerate aging. mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in mice. mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.
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http://dx.doi.org/10.3390/ijms21134667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369923PMC
June 2020

Slc2a10 knock-out mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects.

Hum Mol Genet 2020 06;29(9):1476-1488

Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.

Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicated GLUT10 in the transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations did not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in mouse. Gulo;Slc2a10 double knock-out mice showed mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. Transforming growth factor beta signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 double knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.
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http://dx.doi.org/10.1093/hmg/ddaa071DOI Listing
June 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

Fibulin-4 deficiency differentially affects cytoskeleton structure and dynamics as well as TGFβ signaling.

Cell Signal 2019 06 4;58:65-78. Epub 2019 Mar 4.

Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Fibulin-4 is an extracellular matrix (ECM) protein essential for elastogenesis and mutations in this protein lead to aneurysm formation. In this study, we isolated vascular smooth muscle cells (VSMCs) from mice with reduced fibulin-4 protein expression (Fibulin-4) and from mice with a smooth muscle cell specific deletion of the Fibulin-4 gene (Fibulin-4/SM22Cre). We subsequently analyzed and compared the molecular consequences of reduced Fibulin-4 expression versus total ablation of Fibulin-4 expression with regard to effects on the SMC specific contractile machinery, cellular migration and TGFβ signaling. Analysis of the cytoskeleton showed that while Fibulin-4/SM22Cre VSMCs lack smooth muscle actin (SMA) fibers, Fibulin-4 VSMCs were able to form SMA fibers. Furthermore, Fibulin-4/SM22Cre VSMCs showed a decreased pCofilin to Cofilin ratio, suggesting increased actin depolymerization, while Fibulin-4 VSMCs did not display this decrease. Yet, both Fibulin-4 mutant VSMCs showed decreased migration. We found increased activation of TGFβ signaling in Fibulin-4 VSMCs. However, TGFβ signaling was not increased in Fibulin-4/SM22Cre VSMCs. From these results we conclude that both reduction and absence of Fibulin-4 leads to structural and functional impairment of the SMA cytoskeleton. However, while reduced levels of Fibulin-4 result in increased TGFβ activation, complete absence of Fibulin-4 does not result in increased TGFβ activation. Since both mouse models show thoracic aortic aneurysm formation, we conclude that not only hampered TGFβ signaling, but also SMA cytoskeleton dynamics play an important role in aortic aneurysmal disease.
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http://dx.doi.org/10.1016/j.cellsig.2019.02.008DOI Listing
June 2019

Gestational jet lag predisposes to later-life skeletal and cardiac disease.

Chronobiol Int 2019 05 22;36(5):657-671. Epub 2019 Feb 22.

a Department of Molecular Genetics , University Medical Center Rotterdam , Rotterdam , The Netherlands.

Circadian rhythm disturbance (CRD) increases the risk of disease, e.g. metabolic syndrome, cardiovascular disease, and cancer. In the present study, we investigated later life adverse health effects triggered by repeated jet lag during gestation. Pregnant mice were subjected to a regular light-dark cycle (CTRL) or to a repeated delay (DEL) or advance (ADV) jet lag protocol. Both DEL and ADV offspring showed reduced weight gain. ADV offspring had an increased circadian period, and an altered response to a jet lag was observed in both DEL and ADV offspring. Analysis of the bones of adult male ADV offspring revealed reduced cortical bone mass and strength. Strikingly, analysis of the heart identified structural abnormalities and impaired heart function. Finally, DNA methylation analysis revealed hypermethylation of miR17-92 cluster and differential methylation within circadian clock genes, which correlated with altered gene expression. We show that developmental CRD affects the circadian system and predisposes to non-communicable disease in adult life.
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http://dx.doi.org/10.1080/07420528.2019.1579734DOI Listing
May 2019

Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation.

Cardiovasc Res 2018 11;114(13):1776-1793

Department of Vascular Surgery, Erasmus MC, Wytemaweg 80, CN Rotterdam, The Netherlands.

Aim: Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms underlying aneurysm formation.

Methods And Results: In Fibulin-4R/R mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed proteomics and genomics studies on Fibulin-4R/R mouse aortas. Intriguingly, we observed alterations in mitochondrial protein composition in Fibulin-4R/R aortas. Consistently, functional studies in Fibulin-4R/R vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates. Yet, mitochondria in Fibulin-4R/R VSMCs showed no aberrant cytoplasmic localization. We found similar reduced mitochondrial respiration in Tgfbr-1M318R/+ VSMCs, a mouse model for Loeys-Dietz syndrome (LDS). Interestingly, also human fibroblasts from Marfan (FBN1) and LDS (TGFBR2 and SMAD3) patients showed lower oxygen consumption. While individual mitochondrial Complexes I-V activities were unaltered in Fibulin-4R/R heart and muscle, these tissues showed similar decreased oxygen consumption. Furthermore, aortas of aneurysmal Fibulin-4R/R mice displayed increased reactive oxygen species (ROS) levels. Consistent with these findings, gene expression analyses revealed dysregulation of metabolic pathways. Accordingly, blood ketone levels of Fibulin-4R/R mice were reduced and liver fatty acids were decreased, while liver glycogen was increased, indicating dysregulated metabolism at the organismal level. As predicted by gene expression analysis, the activity of PGC1α, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4R/R VSMCs. Increased TGFβ reduced PGC1α levels, indicating involvement of TGFβ signalling in PGC1α regulation. Activation of PGC1α restored the decreased oxygen consumption in Fibulin-4R/R VSMCs and improved their reduced growth potential, emphasizing the importance of this key regulator.

Conclusion: Our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation.
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http://dx.doi.org/10.1093/cvr/cvy150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198735PMC
November 2018

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

Brain Renin-Angiotensin System: Does It Exist?

Hypertension 2017 06 10;69(6):1136-1144. Epub 2017 Apr 10.

From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine (B.S.v.T., A.G.M., L.t.R., D.S., E.U., I.M.G., F.P.J.L., A.H.J.D.), Department of Vascular Surgery (B.S.v.T., L.t.R., I.v.d.P., J.E.), Department of Molecular Genetics, Cancer Genomics Center Netherlands (B.S.v.T., I.v.d.P., J.E.), Division of Nephrology and Transplantation, Department of Internal Medicine (D.S., E.U.), Department of Radiation Oncology (J.E.), Erasmus MC, Rotterdam, The Netherlands; Department of Molecular Cardiovascular Endocrinology, Max Delbrück Center, Berlin, Germany (F.Q., N.A., M.B.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Germany (N.A., M.B.); Berlin Institute of Health (BIH), Germany (M.B.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Germany (M.B.); Institute of Pathophysiology, Faculty of Medicine, Comenius University (L.P., R.R.); Institute of Normal and Pathophysiological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic (L.P.); and Attoquant Diagnostics (O.D., M.P.) and Department of Internal Medicine III (O.D.), Medical University of Vienna, Austria.

Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08922DOI Listing
June 2017

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

Cell 2017 03;169(1):132-147.e16

Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands; The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA. Electronic address:

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
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http://dx.doi.org/10.1016/j.cell.2017.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182PMC
March 2017

Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging.

PLoS One 2016 8;11(3):e0149941. Epub 2016 Mar 8.

Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149941PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783069PMC
August 2016

AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice.

J Hypertens 2016 Apr;34(4):654-65

aDivision of Vascular Medicine and Pharmacology, Department of Internal Medicine bDepartment of Vascular Surgery cDepartment of Genetics dDepartment of Cardiology eDepartment of Pathology fDepartment of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.

Aims: Increasing evidence supports a role for the angiotensin II-AT1-receptor axis in aneurysm development. Here, we studied whether counteracting this axis via stimulation of AT2 receptors is beneficial. Such stimulation occurs naturally during AT1-receptor blockade with losartan, but not during renin inhibition with aliskiren.

Methods And Results: Aneurysmal homozygous fibulin-4 mice, displaying a four-fold reduced fibulin-4 expression, were treated with placebo, losartan, aliskiren, or the β-blocker propranolol from day 35 to 100. Their phenotype includes cystic media degeneration, aortic regurgitation, left ventricular dilation, reduced ejection fraction, and fractional shortening. Although losartan and aliskiren reduced hemodynamic stress and increased renin similarly, only losartan increased survival. Propranolol had no effect. No drug rescued elastic fiber fragmentation in established aneurysms, although losartan did reduce aneurysm size. Losartan also increased ejection fraction, decreased LV diameter, and reduced cardiac pSmad2 signaling. None of these effects were seen with aliskiren or propranolol. Longitudinal micro-CT measurements, a novel method in which each mouse serves as its own control, revealed that losartan reduced LV growth more than aneurysm growth, presumably because the heart profits both from the local (cardiac) effects of losartan and its effects on aortic root remodeling.

Conclusion: Losartan, but not aliskiren or propranolol, improved survival in fibulin-4 mice. This most likely relates to its capacity to improve structure and function of both aorta and heart. The absence of this effect during aliskiren treatment, despite a similar degree of blood pressure reduction and renin-angiotensin system blockade, suggests that it might be because of AT2-receptor stimulation.
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http://dx.doi.org/10.1097/HJH.0000000000000845DOI Listing
April 2016

The renin-angiotensin system and its involvement in vascular disease.

Eur J Pharmacol 2015 Sep 16;763(Pt A):3-14. Epub 2015 May 16.

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

The renin-angiotensin system (RAS) plays a critical role in the pathogenesis of many types of cardiovascular diseases including cardiomyopathy, valvular heart disease, aneurysms, stroke, coronary artery disease and vascular injury. Besides the classical regulatory effects on blood pressure and sodium homoeostasis, the RAS is involved in the regulation of contractility and remodelling of the vessel wall. Numerous studies have shown beneficial effect of inhibition of this system in the pathogenesis of cardiovascular diseases. However, dysregulation and overexpression of the RAS, through different molecular mechanisms, also induces, the initiation of vascular damage. The key effector peptide of the RAS, angiotensin II (Ang II) promotes cell proliferation, apoptosis, fibrosis, oxidative stress and inflammation, processes known to contribute to remodelling of the vasculature. In this review, we focus on the components that are under the influence of the RAS and contribute to the development and progression of vascular disease; extracellular matrix defects, atherosclerosis and ageing. Furthermore, the beneficial therapeutic effects of inhibition of the RAS on the vasculature are discussed, as well as the need for additive effects on top of RAS inhibition.
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http://dx.doi.org/10.1016/j.ejphar.2015.03.090DOI Listing
September 2015

Cockayne syndrome group B (Csb) and group a (Csa) deficiencies predispose to hearing loss and cochlear hair cell degeneration in mice.

J Neurosci 2015 Mar;35(10):4280-6

Departments of Regenerative Medicine/Stem Cell Biology, and Otolaryngology, Eli and Edythe Broad Center, University of Southern California, Los Angeles, California 90033

Sensory hair cells in the cochlea, like most neuronal populations that are postmitotic, terminally differentiated, and non-regenerating, depend on robust mechanisms of self-renewal for lifelong survival. We report that hair cell homeostasis requires a specific sub-branch of the DNA damage nucleotide excision repair pathway, termed transcription-coupled repair (TCR). Cockayne syndrome (CS), caused by defects in TCR, is a rare DNA repair disorder with a broad clinical spectrum that includes sensorineural hearing loss. We tested hearing and analyzed the cellular integrity of the organ of Corti in two mouse models of this disease with mutations in the Csb gene (CSB(m/m) mice) and Csa gene (Csa(-/-) mice), respectively. Csb(m/m) and Csa(-/-) mice manifested progressive hearing loss, as measured by an increase in auditory brainstem response thresholds. In contrast to wild-type mice, mutant mice showed reduced or absent otoacoustic emissions, suggesting cochlear outer hair cell impairment. Hearing loss in Csb(m/m) and Csa(-/-) mice correlated with progressive hair cell loss in the base of the organ of Corti, starting between 6 and 13 weeks of age, which increased by 16 weeks of age in a basal-to-apical gradient, with outer hair cells more severely affected than inner hair cells. Our data indicate that the hearing loss observed in CS patients is reproduced in mouse models of this disease. We hypothesize that accumulating DNA damage, secondary to the loss of TCR, contributes to susceptibility to hearing loss.
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http://dx.doi.org/10.1523/JNEUROSCI.5063-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355199PMC
March 2015

Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.

PLoS Genet 2014 Oct 9;10(10):e1004686. Epub 2014 Oct 9.

Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.
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http://dx.doi.org/10.1371/journal.pgen.1004686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191938PMC
October 2014

Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.

PLoS One 2014 25;9(9):e106054. Epub 2014 Sep 25.

Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.

Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.

Methods: We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4(R)) mice.

Results: Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4(R/R) mice display severe developmental lung emphysema, whereas Fibulin-4(+/R) mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema.

Conclusions: Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106054PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177830PMC
June 2015

Priming of microglia in a DNA-repair deficient model of accelerated aging.

Neurobiol Aging 2014 Sep 28;35(9):2147-60. Epub 2014 Mar 28.

Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.025DOI Listing
September 2014

Cockayne syndrome pathogenesis: lessons from mouse models.

Mech Ageing Dev 2013 May-Jun;134(5-6):180-95. Epub 2013 Apr 13.

Department of Neuroscience, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

Cockayne syndrome (CS) is a rare multisystem disorder characterized by cachectic dwarfism, nervous system abnormalities and features of premature aging. CS symptoms are associated with mutations in 5 genes, CSA, CSB, XPB, XPD and XPG encoding for proteins involved in the transcription-coupled subpathway of nucleotide excision DNA repair (NER). Mutant mice have been generated for all CS-associated genes and provide tools to examine how the cellular defects translate into CS symptoms. Mice deficient for Csa or Csb genetically mimic CS in man, and develop mild CS symptoms including reduced fat tissue, photoreceptor cell loss, and mild, but characteristic, nervous system pathology. These mild CS models are converted into severe CS models with short life span, progressive nervous system degeneration and cachectic dwarfism after simultaneous complete inactivation of global genome NER. A spectrum of mild-to-severe CS-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines CS symptoms with another NER syndrome, xeroderma pigmentosum. In conclusion, CS mouse models mice develop a range of CS phenotypes and open promising perspectives for testing interventional approaches.
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http://dx.doi.org/10.1016/j.mad.2013.04.003DOI Listing
December 2013

Spatio-temporal analysis of molecular determinants of neuronal degeneration in the aging mouse cerebellum.

Mol Cell Proteomics 2013 May 11;12(5):1350-62. Epub 2013 Feb 11.

Biomolecular Mass Spectrometry and Proteomics Group, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.

The accumulation of cellular damage, including DNA damage, is hypothesized to contribute to aging-related neurodegenerative changes. DNA excision repair cross-complementing group 1 (Ercc1) knock-out mice represent an accepted model of neuronal aging, showing gradual neurodegenerative changes, including loss of synaptic contacts and cell body shrinkage. Here, we used the Purkinje cell-specific Ercc1 DNA-repair knock-out mouse model to study aging in the mouse cerebellum. We performed an in-depth quantitative proteomics analysis, using stable isotope dimethyl labeling, to decipher changes in protein expression between the early (8 weeks), intermediate (16 weeks), and late (26 weeks) stages of the phenotypically aging Ercc1 knock-out and healthy littermate control mice. The expression of over 5,200 proteins from the cerebellum was compared quantitatively, whereby 79 proteins (i.e. 1.5%) were found to be substantially regulated during aging. Nearly all of these molecular markers of the early aging onset belonged to a strongly interconnected network involved in excitatory synaptic signaling. Using immunohistological staining, we obtained temporal and spatial profiles of these markers confirming not only the proteomics data but in addition revealed how the change in protein expression correlates to synaptic changes in the cerebellum. In summary, this study provides a highly comprehensive spatial and temporal view of the dynamic changes in the cerebellum and Purkinje cell signaling in particular, indicating that synapse signaling is one of the first processes to be affected in this premature aging model, leading to neuron morphological changes, neuron degeneration, inflammation, and ultimately behavior disorders.
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http://dx.doi.org/10.1074/mcp.M112.024950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650344PMC
May 2013

The cross talk between pathways in the repair of 8-oxo-7,8-dihydroguanine in mouse and human cells.

Free Radic Biol Med 2012 Dec 7;53(11):2171-7. Epub 2012 Sep 7.

Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Rome, Italy.

Although oxidatively damaged DNA is repaired primarily via the base excision repair (BER) pathway, it is now evident that multiple subpathways are needed. Yet, their relative contributions and coordination are still unclear. Here, mouse embryo fibroblasts (MEFs) from selected nucleotide excision repair (NER) and/or BER mouse mutants with severe (Csb(m/m)/Xpa(-/-) and Csb(m/m)/Xpc(-/-)), mild (Csb(m/m)), or no progeria (Xpa(-/-), Xpc(-/-), Ogg1(-/-), Csb(m/m)/Ogg1(-/-)) or wild-type phenotype were exposed to an oxidizing agent, potassium bromate, and genomic 8-oxo-7,8-dihydroguanine (8-oxoGua) levels were measured by HPLC-ED. The same oxidized DNA base was measured in NER/BER-defective human cell lines obtained after transfection with replicative plasmids encoding siRNA targeting DNA repair genes. We show that both BER and NER factors contribute to the repair of 8-oxoGua, although to different extents, and that the repair profiles are similar in human compared to mouse cells. The BER DNA glycosylase OGG1 dominates 8-oxoGua repair, whereas NER (XPC, XPA) and transcription-coupled repair proteins (CSB and CSA) are similar, but minor contributors. The comparison of DNA oxidation levels in double versus single defective MEFs indicates increased oxidatively damaged DNA only when both CSB and XPC/XPA are defective, indicating that these proteins operate in different pathways. Moreover, we provide the first evidence of an involvement of XPA in the control of oxidatively damaged DNA in human primary cells.
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http://dx.doi.org/10.1016/j.freeradbiomed.2012.08.593DOI Listing
December 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

Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging.

J Proteome Res 2012 Mar 13;11(3):1855-67. Epub 2012 Feb 13.

Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University , De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used Ercc1 mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged Ercc1 mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and Ercc1 mutant hippocampal neurons displayed normal outgrowth and synapse formation in vitro. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline.
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http://dx.doi.org/10.1021/pr201203mDOI Listing
March 2012

Accelerated loss of hearing and vision in the DNA-repair deficient Ercc1(δ/-) mouse.

Mech Ageing Dev 2012 Feb-Mar;133(2-3):59-67. Epub 2012 Jan 12.

Department of Neuroscience, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.

Age-related loss of hearing and vision are two very common disabling conditions, but the underlying mechanisms are still poorly understood. Damage by reactive oxygen species and other reactive cellular metabolites, which in turn may damage macromolecules such as DNA, has been implicated in both processes. To investigate whether DNA damage can contribute to age-related hearing and vision loss, we investigated hearing and vision in Ercc1(δ/-) mutant mice, which are deficient in DNA repair of helix-distorting DNA lesions and interstrand DNA crosslinks. Ercc1(δ/-) mice showed a progressive, accelerated increase of hearing level thresholds over time, most likely arising from deteriorating cochlear function. Ercc1(δ/-) mutants also displayed a progressive decrease in contrast sensitivity followed by thinning of the outer nuclear layer of the eyeball. The strong parallels with normal ageing suggest that unrepaired DNA damage can induce age-related decline of the auditory and visual system.
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http://dx.doi.org/10.1016/j.mad.2011.12.003DOI Listing
July 2012

Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology.

PLoS Genet 2011 Dec 8;7(12):e1002405. Epub 2011 Dec 8.

Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands.

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR-deficient Csa(-/-) and Csb(-/-) CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER-deficient Xpa(-/-) and Xpc(-/-) XP mice, but also occurred in Xpd(XPCS) mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR-deficient mice are compatible with focal dysmyelination in CS patients. Both TCR-deficient and NER-deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa(-/-), Csb(-/-)) or highly sporadic (Xpa(-/-), Xpc(-/-)) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR-deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa(-/-) and Csb(-/-) TCR-deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR-deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
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http://dx.doi.org/10.1371/journal.pgen.1002405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234220PMC
December 2011

Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair.

J Neurosci 2011 Aug;31(35):12543-53

Department of Neuroscience, Erasmus MC, 3015 GE, Rotterdam, The Netherlands, Cancer Genomics Center, Department of Genetics, Center for Biomedical Genetics, Erasmus MC, 3015 GE, Rotterdam, The Netherlands.

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Δ/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.
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http://dx.doi.org/10.1523/JNEUROSCI.1589-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703271PMC
August 2011

Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.

Pathobiol Aging Age Relat Dis 2011 1;1. Epub 2011 Jun 1.

Laboratory of Heath Protection Research, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

Genome maintenance is considered a prime longevity assurance mechanism as apparent from many progeroid human syndromes that are caused by genome maintenance defects. The ERCC1 protein is involved in three genome maintenance systems: nucleotide excision repair, interstrand cross-link repair, and homologous recombination. Here we describe in-life and post-mortem observations for a hypomorphic Ercc1 variant, Ercc1(-/Δ7), which is hemizygous for a single truncated Ercc1 allele, encoding a protein lacking the last seven amino acids. Ercc1(-/Δ7) mice were much smaller and median life span was markedly reduced compared to wild-type siblings: 20 and 118 weeks, respectively. Multiple signs and symptoms of aging were found to occur at an accelerated rate in the Ercc1(-/Δ7) mice as compared to wild-type controls, including a decline in weight of both whole body and various organs, numerous histopathological lesions, and immune parameters. Together they define a segmental progeroid phenotype of the Ercc1(-/Δ7) mouse model.
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http://dx.doi.org/10.3402/pba.v1i0.7219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417667PMC
September 2012

Serum N-glycan profile shift during human ageing.

Exp Gerontol 2010 Oct 27;45(10):738-43. Epub 2010 Aug 27.

Department for Molecular Biomedical Research, VIB, Gent-Zwijnaarde, Belgium.

Biomarkers indicating biological age are of significant interest for prevention, diagnosis and monitoring (and the treatment) of age-related diseases. We previously reported an alteration of serum N-glycan profile in old humans using "DNA Sequencer Adapted-Fluorophore Assisted Carbohydrate Electrophoresis" (DSA-FACE). To validate the shift in serum N-glycan profile during ageing, we studied serum N-glycan profiles in different age groups of healthy volunteers, patients with dementia, and patients with Cockayne syndrome, a genetic DNA repair disorder involving neurodegeneration and premature ageing. We found that the log of the ratio of two glycans (NGA2F and NA2F), named GlycoAgeTest, remained steady up to the age of 40years and thereafter gradually increased to reach its highest level in nonagenarians. Patients with dementia or Cockayne syndrome had a higher GlycoAgeTest level than age-matched healthy individuals. We thus demonstrate that the value of GlycoAgeTest is better than chronological age for estimating the physiological age of a human individual, and that it could be used as an ageing biomarker for healthy humans. Our data indicate that the GlycoAgeTest could be used as a non-invasive surrogate marker for general health, for forecasting disease progression during ageing, and for monitoring the efficacy of anti-ageing food compounds.
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http://dx.doi.org/10.1016/j.exger.2010.08.009DOI Listing
October 2010
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