Selective Phosphodiesterase 1 Inhibition Ameliorates Vascular Function, Reduces Inflammatory Response, and Lowers Blood Pressure in Aging Animals

Abstract

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 Ercc1 Δ/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 Ercc1 Δ/mice. Compared to wild-type mice, Ercc1 Δ/mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endotheliumdependent 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 Ercc1 Δ/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 Ercc1 Δ/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.

The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features

“…The involvement of other cell types than VSMC is also supported by the differential effect of lenrispodun on plasma cytokines in Ercc1 Δ/mice vs. SMC-KO. Cytokines IL-1β and TNF-α were increased in Ercc1 Δ/mice (Golshiri et al, 2021) and inhibited by lenrispodun. These cytokines were unchanged in SMC-KO, both by genotype and treatment, implicating a non-VSMC origin in Ercc1 Δ/mice.…”

“…In Ercc1 Δ/mice, the effect of chronic PDE1 inhibition was sustained after removal of the arterial tissue and subsequent measurement in the organ bath. This discrepancy might be explained by the predominant role and more advanced state of VSMC dysfunction in the aorta of SMC-KO (39% loss of response to 0.1 mM SNP) compared to Ercc1 Δ/mice (21% loss of response to 0.1 mM SNP (Golshiri et al, 2021)). The Ercc1 Δ/mutation preserved one allele that produces a partially active, mutant ERCC1 protein, whereas the presently used SMC-KO is a full gene knockout.…”

“…Our previous work applying acute ex vivo tests with PDE1 inhibitors suggested that PDE1 might underlie the development of vasomotor dysfunction during aging (Bautista Niño et al, 2015). Our recent examination of the effects of acute and chronic PDE1 inhibition in a mouse model of accelerated aging showed an acute contribution to vasodilation specifically in aged mice, and protection against aging-related vasomotor dysfunction after chronic treatment (Golshiri et al, 2021). It is unclear however if this effect is mediated through a specific effect on smooth muscle cells.…”

Soluble guanylate cyclase activator BAY 54–6544 improves vasomotor function and survival in an accelerated ageing mouse model

“…Vasodilator responses to BAY 41–8543 and BAY 60–2770 were similar in untreated Ercc1 Δ/− vs. WT mice, and therefore heme‐oxidation did not seem to play a role. We previously found increased phosphodiesterase (PDE) metabolism of cGMP to be responsible for decreased NO—cGMP signaling in Ercc1 Δ/− vascular tissue, and treatment with inhibitors thereof to exert beneficial vascular effects (Golshiri, Ataabadi, et al, 2021 ; Golshiri, Ataei Ataabadi, Brandt, et al, 2020 ; Golshiri, Ataei Ataabadi, et al, 2021 ). Our present results in aortic tissue organ bath experiments show that acute stimulation with BAY 41–8543 and BAY 60–2770 overcomes the phosphodiesterase increase and leads to up to 100% relaxation of the preconstriction with U46619 vs. 60–80% relaxation with SNP.…”

“…Vasodilator responses to BAY 41-8543 and BAY 60-2770 were similar in untreated Ercc1 Δ/− vs. WT mice, and therefore hemeoxidation did not seem to play a role. We previously found increased phosphodiesterase (PDE) metabolism of cGMP to be responsible for decreased NO-cGMP signaling in Ercc1 Δ/− vascular tissue, and treatment with inhibitors thereof to exert beneficial vascular effects Golshiri, Ataei Ataabadi, Brandt, et al, 2020;Golshiri, Ataei Ataabadi, et al, 2021). SNP responses are limited by PDE and sGC nitrosylation in VSMC.…”