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 (Ercc1d/− mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1d/− 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 Ercc1d/− to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1d/− mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1d/− 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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October 13 2015
Phosphodiesterase 1 regulation is a key mechanism in vascular aging
Paula K. Bautista Niño;
Paula K. Bautista Niño
1
*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
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Matej Durik;
Matej Durik
1
*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
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A.H. Jan Danser;
A.H. Jan Danser
*Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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René de Vries;
René de Vries
*Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Usha M. Musterd-Bhaggoe;
Usha M. Musterd-Bhaggoe
*Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Marcel E. Meima;
Marcel E. Meima
§Department of Internal Medicine, Division of Endocrinology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Maryam Kavousi;
Maryam Kavousi
†Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Mohsen Ghanbari;
Mohsen Ghanbari
†Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Jan H. Hoeijmakers;
Jan H. Hoeijmakers
║Department of Genetics, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Christopher J. O'Donnell;
Christopher J. O'Donnell
¶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.
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Nora Franceschini;
Nora Franceschini
‡‡Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599-7435, U.S.A.
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Ger M.J. Janssen;
Ger M.J. Janssen
§§Department of Pharmacology, Maastricht University, 6211 LK, The Netherlands
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Jo G.R. De Mey;
Jo G.R. De Mey
§§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
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Yiwen Liu;
Yiwen Liu
¶¶Cardiovascular Division, James Black Centre, King's College, London SE5 9NU, U.K.
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Catherine M. Shanahan;
Catherine M. Shanahan
¶¶Cardiovascular Division, James Black Centre, King's College, London SE5 9NU, U.K.
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Oscar H. Franco;
Oscar H. Franco
†Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Abbas Dehghan;
Abbas Dehghan
†Department of Epidemiology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
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Anton J.M. Roks
*Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus MC Rotterdam, 3015 CN, The Netherlands
Correspondence: Dr Anton Roks (email [email protected]).
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Publisher: Portland Press Ltd
Received:
November 19 2014
Revision Received:
June 03 2015
Accepted:
June 25 2015
Accepted Manuscript online:
July 25 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (12): 1061–1075.
Article history
Received:
November 19 2014
Revision Received:
June 03 2015
Accepted:
June 25 2015
Accepted Manuscript online:
July 25 2015
Connected Content
This is a commentary on:
Cyclic nucleotide phosphodiesterase 1 and vascular aging
Citation
Paula K. Bautista Niño, Matej Durik, A.H. Jan Danser, René de Vries, Usha M. Musterd-Bhaggoe, Marcel E. Meima, Maryam Kavousi, Mohsen Ghanbari, Jan H. Hoeijmakers, Christopher J. O'Donnell, Nora Franceschini, Ger M.J. Janssen, Jo G.R. De Mey, Yiwen Liu, Catherine M. Shanahan, Oscar H. Franco, Abbas Dehghan, Anton J.M. Roks; Phosphodiesterase 1 regulation is a key mechanism in vascular aging. Clin Sci (Lond) 1 December 2015; 129 (12): 1061–1075. doi: https://doi.org/10.1042/CS20140753
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