Phosphodiesterase 1 regulation is a key mechanism in vascular aging

Clin Sci (Lond). 2015 Dec;129(12):1061-75. doi: 10.1042/CS20140753. Epub 2015 Jun 25.

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.

Keywords: aging; blood pressure; genetic association; phosphodiesterases; vascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Blood Pressure
  • Carotid Arteries / enzymology
  • Carotid Arteries / pathology
  • Carotid Artery Diseases / enzymology
  • Carotid Artery Diseases / genetics
  • Carotid Artery Diseases / pathology
  • Carotid Intima-Media Thickness
  • Cells, Cultured
  • Cellular Senescence
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / antagonists & inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Dose-Response Relationship, Drug
  • Endonucleases / deficiency
  • Endonucleases / genetics
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Hydrolysis
  • Hyperplasia
  • Hypertension / enzymology
  • Hypertension / genetics
  • Hypertension / physiopathology
  • In Vitro Techniques
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • Phenotype
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Polymorphism, Single Nucleotide
  • Second Messenger Systems
  • Vasodilation* / drug effects
  • Vasodilator Agents / pharmacology

Substances

  • DNA-Binding Proteins
  • Phosphodiesterase 5 Inhibitors
  • Vasodilator Agents
  • Endonucleases
  • Ercc1 protein, mouse
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • PDE1A protein, human
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic GMP