{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:17:58Z","timestamp":1790507878021,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:00:00Z","timestamp":1689120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Diabetes mellitus (DM) is an independent risk factor for micro- and macrovascular complications such as nephropathy and atherosclerosis respectively, which are the major causes of premature morbidity and mortality in Type 1 and Type 2 diabetic patients. Endothelial dysfunction is the critical first step of vascular disease and is characterized by reduced bioavailability of the essential endothelial vasodilator, nitric oxide (NO), coupled with an elevation in inflammation and oxidative stress. A novel pathway to bolster NO activity is to upregulate soluble guanylate cyclase (sGC), an enzyme responsible for mediating the protective actions of NO. Two classes of sGC modulators exist, activators and stimulators, with differing sensitivity to oxidative stress. In this study, we investigated the therapeutic effects of the sGC stimulator BAY 41-2272 (Bay 41) and the sGC activator BAY 60-2770 (Bay 60) on endpoints of atherosclerosis and renal disease as well as inflammation and oxidative stress in diabetic Apolipoprotein E knockout (ApoE-\/-) mice. We hypothesized that under oxidative conditions known to accompany diabetes, sGC activation might be more efficacious than sGC stimulation in limiting diabetic vascular complications. We demonstrate that Bay 60 not only significantly decreased nitrotyrosine staining (<jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.01) and F4\/80 positive cells by 75% (<jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.05), but it also significantly reduced total plaque area (<jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.05) and improved endothelial function (<jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.01). Our data suggest an important anti-atherogenic role for Bay 60 accompanied by reduced oxidative stress and inflammation under diabetic settings. Treatment with the stimulator Bay 41, on the other hand, had minimal effects or caused no changes with respect to cardiovascular or renal pathology. In the kidneys, treatment with Bay 60 significantly lessened urinary albuminuria, mesangial expansion and nitrotyrosine staining under diabetic conditions. In summary, our head-to-head comparator is the first preclinical study to show that a sGC activator is more efficacious than a sGC stimulator for the treatment of diabetes-associated vascular and renal complications.<\/jats:p>","DOI":"10.3389\/fcvm.2023.1220095","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T20:03:15Z","timestamp":1689192195000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Ameliorating diabetes-associated atherosclerosis and diabetic nephropathy through modulation of soluble guanylate cyclase"],"prefix":"10.3389","volume":"10","author":[{"given":"Arpeeta","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan","family":"Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhiroop","family":"Dey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthukumar","family":"Mohan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Kantharidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Dietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sandner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy B.","family":"de Haan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,12]]},"reference":[{"key":"B1","volume-title":"IDF Diabetes atlas. 10th ed.","author":"Federation","year":"2021"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s12933-017-0497-7","article-title":"The renal tubular damage marker urinary N-acetyl-beta-D-glucosaminidase may be more closely associated with early detection of atherosclerosis than the glomerular damage marker albuminuria in patients with type 2 diabetes","volume":"16","author":"Kim","year":"2017","journal-title":"Cardiovasc Diabetol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S186","DOI":"10.1053\/ajkd.2001.2744","article-title":"Renal insufficiency accelerates atherosclerosis in patients with type 2 diabetes mellitus","volume":"38","author":"Ishimura","year":"2001","journal-title":"Am J Kidney Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1111\/j.1463-1326.2007.00727.x","article-title":"A cardiologist view of vascular disease in diabetes","volume":"10","author":"Lockhart","year":"2008","journal-title":"Diabetes Obes Metab"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1161\/CIRCULATIONAHA.108.835223","article-title":"Molecular insights and therapeutic targets for diabetic endothelial dysfunction","volume":"120","author":"Xu","year":"2009","journal-title":"Circulation"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/bs.apha.2016.05.001","article-title":"The endothelium-dependent nitric oxide-cGMP pathway","volume":"77","author":"Monica","year":"2016","journal-title":"Adv Pharmacol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1093\/clinchem\/44.8.1809","article-title":"Role of nitric oxide in cardiovascular disease: focus on the endothelium","volume":"44","author":"Cannon","year":"1998","journal-title":"Clin Chem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1161\/CIRCULATIONAHA.105.602532","article-title":"Endothelial nitric oxide synthase in vascular disease: from marvel to menace","volume":"113","author":"Forstermann","year":"2006","journal-title":"Circulation"},{"key":"B9","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1161\/CIRCULATIONAHA.117.028021","article-title":"Phenotypic consequences of a genetic predisposition to enhanced nitric oxide signaling","volume":"137","author":"Emdin","year":"2018","journal-title":"Circulation"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3937","DOI":"10.2337\/db15-0472","article-title":"Direct endothelial nitric oxide synthase activation provides atheroprotection in diabetes-accelerated atherosclerosis","volume":"64","author":"Sharma","year":"2015","journal-title":"Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19061712","article-title":"The impact of the nitric oxide (NO)\/soluble guanylyl cyclase (sGC) signaling cascade on kidney health and disease: a preclinical perspective","volume":"19","author":"Krishnan","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0735-1097(00)00743-9","article-title":"Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study","volume":"36","author":"Mullen","year":"2000","journal-title":"J Am Coll Cardiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"667","DOI":"10.7326\/0003-4819-114-8-667","article-title":"Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention","volume":"114","author":"Elkayam","year":"1991","journal-title":"Ann Intern Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15698","article-title":"Soluble GC stimulators and activators: past, present and future","author":"Sandner","year":"2021","journal-title":"Br J Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"12938","DOI":"10.1073\/pnas.231486198","article-title":"YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components","volume":"98","author":"Martin","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1161\/CIRCULATIONAHA.110.981738","article-title":"Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease","volume":"123","author":"Stasch","year":"2011","journal-title":"Circulation"},{"key":"B17","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1159\/000450946","article-title":"The potential of sGC modulators for the treatment of age-related fibrosis: a Mini-review","volume":"63","author":"Sandner","year":"2017","journal-title":"Gerontology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1056\/NEJMoa1209655","article-title":"Riociguat for the treatment of pulmonary arterial hypertension","volume":"369","author":"Ghofrani","year":"2013","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"128","DOI":"10.3389\/fphar.2012.00128","article-title":"Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress","volume":"3","author":"Costell","year":"2012","journal-title":"Front Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"v","DOI":"10.1007\/978-3-540-68964-5","article-title":"Handbook of experimental pharmacology 191. cGMP: generators, effectors and therapeutic implications. Preface","volume":"101","author":"Schmidt","year":"","journal-title":"Handb Exp Pharmacol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1038\/s44161-022-00175-w","article-title":"Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation","volume":"1","author":"Mauersberger","year":"2022","journal-title":"Nat Cardiovasc Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1111\/apha.12210","article-title":"Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis","volume":"210","author":"Tsou","year":"2014","journal-title":"Acta Physiol (Oxf)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/hr.2009.64","article-title":"Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart","volume":"32","author":"Masuyama","year":"2009","journal-title":"Hypertens Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s00395-014-0421-1","article-title":"Soluble guanylyl cyclase activation improves progressive cardiac remodeling and failure after myocardial infarction. Cardioprotection over ACE inhibition","volume":"109","author":"Fraccarollo","year":"2014","journal-title":"Basic Res Cardiol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1097\/FJC.0b013e31819715c4","article-title":"Antigrowth properties of BAY 41-2272 in vascular smooth muscle cells","volume":"53","author":"Mendelev","year":"2009","journal-title":"J Cardiovasc Pharmacol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1124\/jpet.111.183400","article-title":"The soluble guanylate cyclase stimulator BAY 41-2272 inhibits vascular smooth muscle growth through the cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways","volume":"339","author":"Joshi","year":"2011","journal-title":"J Pharmacol Exp Ther"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1007\/s00210-021-02149-4","article-title":"Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease","volume":"394","author":"Benardeau","year":"2021","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.coph.2014.12.014","article-title":"Renal effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence","volume":"21","author":"Stasch","year":"2015","journal-title":"Curr Opin Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/35065611","article-title":"NO-independent regulatory site on soluble guanylate cyclase","volume":"410","author":"Stasch","year":"2001","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12933-017-0513-y","article-title":"The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction","volume":"16","author":"Sharma","year":"2017","journal-title":"Cardiovasc Diabetol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1161\/ATVBAHA.109.186619","article-title":"Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E-deficient mouse","volume":"29","author":"Chew","year":"2009","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"772","DOI":"10.2337\/db20-0357","article-title":"Specific NLRP3 inhibition protects against diabetes-associated atherosclerosis","volume":"70","author":"Sharma","year":"2021","journal-title":"Diabetes"},{"key":"B33","doi-asserted-by":"publisher","first-page":"8741","DOI":"10.1038\/s41598-023-35680-w","article-title":"Cardiovascular characterisation of a novel mouse model that combines hypertension and diabetes co-morbidities","volume":"13","author":"Sharma","year":"2023","journal-title":"Sci Rep"},{"key":"B34","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1161\/CIRCRESAHA.120.316653","article-title":"Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis","volume":"127","author":"Flynn","year":"2020","journal-title":"Circ Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1161\/ATVBAHA.114.303564","article-title":"Neutrophils in atherosclerosis: from mice to man","volume":"35","author":"Doring","year":"2015","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"F685","DOI":"10.1152\/ajprenal.00280.2004","article-title":"Stimulation of soluble guanylyl cyclase inhibits mesangial cell proliferation and matrix accumulation in experimental glomerulonephritis","volume":"288","author":"Hohenstein","year":"2005","journal-title":"Am J Physiol Renal Physiol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1038\/sj.bjp.0706792","article-title":"NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5\/6 nephrectomy","volume":"148","author":"Kalk","year":"2006","journal-title":"Br J Pharmacol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.semnephrol.2010.03.007","article-title":"Macrophages and diabetic nephropathy","volume":"30","author":"Tesch","year":"2010","journal-title":"Semin Nephrol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2152","DOI":"10.2337\/db09-1772","article-title":"Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy","volume":"59","author":"Tessari","year":"2010","journal-title":"Diabetes"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1220095\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T20:03:19Z","timestamp":1689192199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1220095\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,12]]},"references-count":39,"alternative-id":["10.3389\/fcvm.2023.1220095"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2023.1220095","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,12]]},"article-number":"1220095"}}