title: Phosphodiesterase 1 regulation is a key mechanism in vascular aging.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Paula K
authors.initials: PK
authors.lastname: Bautista Niño
authors.affiliation: Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic.
authors.forename: Matej
authors.initials: M
authors.lastname: Durik
authors.affiliation: Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Usha M
authors.initials: UM
authors.lastname: Musterd-Bhaggoe
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Meima
authors.affiliation: Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Maryam
authors.initials: M
authors.lastname: Kavousi
authors.affiliation: Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanbari
authors.affiliation: Department of Genetics, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702-5827, U.S.A. National Heart, Lung, and Blood Institute, Bethesda, MD 20892, U.S.A. Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, U.S.A.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599-7435, U.S.A.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Pharmacology, Maastricht University, 6211 LK, The Netherlands.
authors.forename: Ger M J
authors.initials: GM
authors.lastname: Janssen
authors.affiliation: Department of Pharmacology, Maastricht University, 6211 LK, The Netherlands Department of Cardiovascular and Renal research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark.
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
authors.affiliation: Cardiovascular Division, James Black Centre, King's College, London SE5 9NU, U.K.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cardiovascular Division, James Black Centre, King's College, London SE5 9NU, U.K.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.affiliation: Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands a.roks@erasmusmc.nl.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Roks
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D059168:Carotid Intima-Media Thickness; D002478:Cells, Cultured; D016922:Cellular Senescence; D006152:Cyclic GMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006868:Hydrolysis; D006965:Hyperplasia; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D015290:Second Messenger Systems; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517265:PDE1A protein, human; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
keywords: aging; blood pressure; genetic association; phosphodiesterases; vascular disease