{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:30:11Z","timestamp":1784259011611,"version":"3.55.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1\u03b1 to counteract cardiac hypertrophy and failure. PKG1\u03b1 acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1\u03b1 oxidation might also differentially influence the effects from their pharmacological modulation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              Knock-in mice expressing a redox-dead PKG1\u03b1 (PKG1\u03b1\n              <jats:sup>C42S<\/jats:sup>\n              ) or littermate controls (PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              ) were subjected to transaortic constriction to induce pressure overload and treated with a PDE5 inhibitor (sildenafil), sGC activator (BAY602770 [BAY]), or vehicle. In PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              controls, sildenafil and BAY similarly enhanced PKG activity and reduced pathological hypertrophy\/fibrosis and cardiac dysfunction after transaortic constriction. However, sildenafil failed to protect the heart in PKG1\u03b1\n              <jats:sup>C42S<\/jats:sup>\n              , unlike BAY, which activated PKG and thereby facilitated protective effects. This corresponded with minimal PDE5 activation in PKG1\u03b1\n              <jats:sup>C42S<\/jats:sup>\n              exposed to transaortic constriction versus higher activity in controls and little colocalization of PDE5 with PKG1\u03b1\n              <jats:sup>C42S<\/jats:sup>\n              (versus colocalization with PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              ) in stressed myocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>In the stressed heart and myocytes, PKG1\u03b1 C42-disulfide formation contributes to PDE5 activation. This augments the pathological role of PDE5 and so in turn enhances the therapeutic impact from its inhibition. PKG1\u03b1 oxidation does not change the benefits from sGC activation. This finding favors the use of sGC activators regardless of PKG1\u03b1 oxidation and may help guide precision therapy leveraging the cyclic GMP\/PKG pathway to treat heart disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.117.004740","type":"journal-article","created":{"date-parts":[[2018,3,15]],"date-time":"2018-03-15T09:15:13Z","timestamp":1521105313000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Prevention of PKG-1\u03b1 Oxidation Suppresses Antihypertrophic\/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation"],"prefix":"10.1161","volume":"11","author":[{"given":"Taishi","family":"Nakamura","sequence":"first","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangshuo","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Ranek","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Kokkonen-Simon","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manling","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace E.","family":"Kim","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Tsujita","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N., K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kass","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (T.N., G.Z., M.J.R., K.K.-S., M.Z., G.E.K., D.A.K.); 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