Abstract 9317: Soluble Guanylate Cyclase Activator Treatment Improves Vasomotor Function in an Accelerated-Ageing Mouse Model

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Introduction: Vascular ageing is a key driver of cardiovascular diseases. Mice with partial deletion of the repair enzyme gene Ercc1 ( Ercc1 Δ/- ) display accelerated vascular ageing which is associated with decreased nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling, oxidative stress, inflammation, and cellular senescence. Restoring this pathway could be an effective treatment opportunity for vascular ageing. We therefore, investigated the therapeutic potential of the sGC activator BAY 56-6544, which can activate oxidized and heme-free sGC in Ercc1 Δ/- mice. Design and Method: Ercc1 Δ/- and wild-type (WT) mice received either vehicle or BAY 54-6544 chow for 8 weeks. Blood pressure (BP) and in-vivo vasodilation (reactive hyperemia: RH) were measured at 15 and 16 weeks respectively. Mice were sacrificed at 17 weeks. Thoracic aorta (TA) endothelium-dependent (ED) and -independent (EI) relaxations were assessed (wire-myograph). Afterwards, we investigated the expression level of senescent markers p16 and p21 and inflammatory markers Il-6 and Ccl2 in aorta by qPCR. Results: BP was similar in all groups. RH was decreased in Ercc1 Δ/- vs. WT (P=0.03) and significantly improved after BAY 54-6544 treatment to the same level as in WT. In vehicle-treated Ercc1 Δ/- mice maximal NO-mediated relaxation in TA to acetylcholine (ED) and sodium nitroprusside (EI) were decreased as compared to WT (ED: 46.97±7.04 vs. 72.33±3.03, P=0.0001; EI: 75.47±5.27 vs. 88.30±3.64, P=0.02). Although BAY 54-6544 treatment did not improve ED response significantly, it improved EI relaxation in Ercc1 Δ/- to the same level as in WT (EI 88.54±3.26). EI response in BAY 54-6544-treated WT was the same as in vehicle-treated one (86.98±3.56). mRNA expression of p16, p21 and Ccl2 were significantly higher in vehicle-treated Ercc1 Δ/- , whereas BAY 54-6544 treatment could attenuate this increase. Conclusion: DNA repair deficiency in Ercc1 Δ/- mice causes a disruption of NO-sGC-cGMP signaling and a decrease of vasodilator response. Treatment with the BAY 54-6544 improved NO-mediated vasodilation and attenuated vascular senescence and inflammation markers. Thus, BAY 54-6544 could be a potential therapeutic treatment to attenuate vascular ageing.