TY - JOUR
T1 - Soluble guanylate cyclase activator BAY 54–6544 improves vasomotor function and survival in an accelerated ageing mouse model
AU - Ataei Ataabadi, Ehsan
AU - Golshiri, Keivan
AU - Jüttner, Annika A.
AU - de Vries, René
AU - Van den Berg-Garrelds, Ingrid
AU - Nagtzaam, Nicole M.A.
AU - Khan, Hina N.
AU - Leijten, Frank P.J.
AU - Brandt, Renata M.C.
AU - Dik, Willem A.
AU - van der Pluijm, Ingrid
AU - Danser, A. H.Jan
AU - Sandner, Peter
AU - Roks, Anton J.M.
N1 - ACKNOWLEDGMENTS
A.J.M.R, E.A.A., and K.G., were supported by grant #60 from “Stichting Lijf & Leven”, the Netherlands.
Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2022/9
Y1 - 2022/9
N2 - DNA damage is a causative factor in ageing of the vasculature and other organs. One of the most important vascular ageing features is reduced nitric oxide (NO)soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) signaling. We hypothesized that the restoration of NO-sGC-cGMP signaling with an sGC activator (BAY 54–6544) may have beneficial effects on vascular ageing and premature death in DNA repair-defective mice undergoing accelerated ageing. Eight weeks of treatment with a non-pressor dosage of BAY 54–6544 restored the decreased in vivo microvascular cutaneous perfusion in progeroid Ercc1∆/− mice to the level of wild-type mice. In addition, BAY 54–6544 increased survival of Ercc1∆/− mice. In isolated Ercc1∆/− aorta, the decreased endothelium-independent vasodilation was restored after chronic BAY 54–6544 treatment. Senescence markers p16 and p21, and markers of inflammation, including Ccl2, Il6 in aorta and liver, and circulating IL-6 and TNF-α were increased in Ercc1∆/−, which was lowered by the treatment. Expression of antioxidant genes, including Cyb5r3 and Nqo1, was favorably changed by chronic BAY 54–6544 treatment. In summary, BAY 54–6544 treatment improved the vascular function and survival rates in mice with accelerated ageing, which may have implication in prolonging health span in progeria and normal ageing.
AB - DNA damage is a causative factor in ageing of the vasculature and other organs. One of the most important vascular ageing features is reduced nitric oxide (NO)soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) signaling. We hypothesized that the restoration of NO-sGC-cGMP signaling with an sGC activator (BAY 54–6544) may have beneficial effects on vascular ageing and premature death in DNA repair-defective mice undergoing accelerated ageing. Eight weeks of treatment with a non-pressor dosage of BAY 54–6544 restored the decreased in vivo microvascular cutaneous perfusion in progeroid Ercc1∆/− mice to the level of wild-type mice. In addition, BAY 54–6544 increased survival of Ercc1∆/− mice. In isolated Ercc1∆/− aorta, the decreased endothelium-independent vasodilation was restored after chronic BAY 54–6544 treatment. Senescence markers p16 and p21, and markers of inflammation, including Ccl2, Il6 in aorta and liver, and circulating IL-6 and TNF-α were increased in Ercc1∆/−, which was lowered by the treatment. Expression of antioxidant genes, including Cyb5r3 and Nqo1, was favorably changed by chronic BAY 54–6544 treatment. In summary, BAY 54–6544 treatment improved the vascular function and survival rates in mice with accelerated ageing, which may have implication in prolonging health span in progeria and normal ageing.
UR - http://www.scopus.com/inward/record.url?scp=85136717859&partnerID=8YFLogxK
U2 - 10.1111/acel.13683
DO - 10.1111/acel.13683
M3 - Article
C2 - 36029161
AN - SCOPUS:85136717859
SN - 1474-9718
VL - 21
JO - Aging Cell
JF - Aging Cell
IS - 9
M1 - e13683
ER -