{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:14:29Z","timestamp":1792088069471,"version":"4.4.0"},"reference-count":66,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg\/kg\/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4\u201312 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton\u2019s index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside\u2013induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.<\/jats:p>","DOI":"10.1165\/rcmb.2017-0292oc","type":"journal-article","created":{"date-parts":[[2017,12,21]],"date-time":"2017-12-21T17:22:39Z","timestamp":1513876959000},"page":"636-647","source":"Crossref","is-referenced-by-count":34,"title":["Nitric Oxide\u2013Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease"],"prefix":"10.1093","volume":"58","author":[{"given":"Karin P.","family":"Potoka","sequence":"first","affiliation":[{"name":"Division of Newborn Medicine, Department of Pediatrics"},{"name":"Heart, Lung, Blood, and Vascular Medicine Institute, Department of 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Witten\/Herdecke, Witten, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Wittwer","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Stampfuss","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Mathar","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes-Peter","family":"Stasch","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany"},{"name":"University of Halle, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Truebel","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany"},{"name":"University of Witten\/Herdecke, Witten, 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