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.

• MeSH
• arteriae carotides enzymologie   patologie   MeSH
• celogenomová asociační studie MeSH
• cyklické nukleotidfosfodiesterasy, typ 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• cyklické nukleotidfosfodiesterasy, typ 5 genetika   metabolismus   MeSH
• DNA vazebné proteiny nedostatek   genetika   MeSH
• endonukleasy nedostatek   genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• guanosinmonofosfát cyklický metabolismus   MeSH
• hydrolýza MeSH
• hyperplazie MeSH
• hypertenze enzymologie   genetika   patofyziologie   MeSH
• inhibitory fosfodiesterasy 5 farmakologie   MeSH
• intimomediální šíře tepenné stěny MeSH
• jednonukleotidový polymorfismus MeSH
• krevní tlak MeSH
• kultivované buňky MeSH
• lidé MeSH
• myocyty hladké svaloviny účinky léků   enzymologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• nemoci arterie carotis enzymologie   genetika   patologie   MeSH
• regulace genové exprese u nádorů MeSH
• stárnutí buněk MeSH
• stárnutí genetika   metabolismus   MeSH
• svaly hladké cévní účinky léků   enzymologie   MeSH
• systémy druhého messengeru MeSH
• techniky in vitro MeSH
• vazodilatace * účinky léků   MeSH
• vazodilatancia farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH