{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:08Z","timestamp":1787018348579,"version":"build-2736575974"},"reference-count":54,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["HL18183"],"award-info":[{"award-number":["HL18183"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK107220"],"award-info":[{"award-number":["DK107220"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,22]]},"abstract":"<jats:p>\n                    cGMP-dependent protein kinase 1\u03b1 (PKG1\u03b1) promotes left ventricle (LV) compensation after pressure overload. PKG1-activating drugs improve heart failure (HF) outcomes but are limited by vasodilation-induced hypotension. Signaling molecules that mediate PKG1\u03b1 cardiac therapeutic effects but do not promote PKG1\u03b1-induced hypotension could therefore represent improved therapeutic targets. We investigated roles of mixed lineage kinase 3 (MLK3) in mediating PKG1\u03b1 effects on LV function after pressure overload and in regulating BP. In a transaortic constriction HF model, PKG activation with sildenafil preserved LV function in MLK3\n                    <jats:sup>+\/+<\/jats:sup>\n                    but not MLK3\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    littermates. MLK3 coimmunoprecipitated with PKG1\u03b1. MLK3-PKG1\u03b1 cointeraction decreased in failing LVs. PKG1\u03b1 phosphorylated MLK3 on Thr277\/Ser281 sites required for kinase activation. MLK3\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the soluble guanylate cyclase (sGC) stimulator BAY41-2272 still reduced BP in MLK3\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice. MLK3 kinase inhibition with URMC-099 did not affect BP but induced LV dysfunction in mice. These data reveal MLK3 as a PKG1\u03b1 substrate mediating PKG1\u03b1 preservation of LV function but not acute PKG1\u03b1 BP effects. Mechanistically, MLK3 kinase\u2013dependent effects preserved LV function, whereas MLK3 kinase\u2013independent signaling regulated BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1\u03b1 activation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.149075","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T12:01:19Z","timestamp":1627560079000},"source":"Crossref","is-referenced-by-count":8,"title":["MLK3 mediates impact of PKG1\u03b1 on cardiac function and controls blood pressure through separate mechanisms"],"prefix":"10.1172","volume":"6","author":[{"given":"Timothy D.","family":"Calamaras","sequence":"first","affiliation":[{"name":"Molecular Cardiology Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suchita","family":"Pande","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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