RT Journal Article
SR Electronic
T1 Selective PDE1 inhibition ameliorates vascular function, reduces inflammatory response, and lowers blood pressure in ageing animals
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2021-000628
DO 10.1124/jpet.121.000628
A1 Keivan Golshiri
A1 Ehsan Ataei Ataabadi
A1 Eloísa Rubio-Beltran
A1 Sophie Dutheil
A1 Wei Yao
A1 Gretchen L Snyder
A1 Robert E Davis
A1 Ingrid van der Pluijm
A1 Renata Brandt
A1 Ingrid M van den Berg - Garrelds
A1 Antoinette MaassenVanDenBrink
A1 René de Vries
A1 A.H. Jan Danser
A1 Anton J. M. Roks
YR 2021
UL http://jpet.aspetjournals.org/content/early/2021/06/04/jpet.121.000628.abstract
AB 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 Ercc1Δ/- 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 Ercc1Δ/- mice. Compared to wild-type mice, Ercc1Δ/- 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 Ercc1Δ/- 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 Ercc1Δ/- 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. Significance Statement 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.