{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:43:46Z","timestamp":1793054626275,"version":"4.5.0"},"reference-count":85,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":43,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL167778"],"award-info":[{"award-number":["R01HL167778"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F31HL165180"],"award-info":[{"award-number":["F31HL165180"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["898429"],"award-info":[{"award-number":["898429"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,22]]},"abstract":"<jats:p>\n                    Cardiac hypertrophy is a common adaptation to cardiovascular stress and often a prelude to heart failure. We examined how\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylation of the small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), impacts cardiomyocyte stress signaling. Mutation of the Cys-178 palmitoylation site impaired activation of Rac1 when overexpressed in cardiomyocytes. Cardiomyocyte-specific Rac1 conditional knockin (Rac1\n                    <jats:sup>cKI<\/jats:sup>\n                    ) mice expressing a Rac1\n                    <jats:sup>C178S<\/jats:sup>\n                    mutant protein exhibited normal cardiac structure and function but developed more severe cardiac hypertrophy in response to angiotensin II (AngII) infusion, cardiomyocyte-specific overexpression of AngII type 1 receptor (AT1R), and cardiac pressure overload. Moreover, pressure overload and AT1R overexpression evoked cardiac failure phenotypes in Rac1\n                    <jats:sup>cKI<\/jats:sup>\n                    mice not observed in controls. Mechanistically, Rac1\n                    <jats:sup>cKI<\/jats:sup>\n                    hearts and cardiomyocytes genetically resistant to Rac1\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylation had a profound increase in protein kinase A (PKA) substrate phosphorylation in response to acute \u03b2-adrenergic stimulation, as did Rac1\n                    <jats:sup>cKI<\/jats:sup>\n                    hearts subjected to chronic AngII treatment, AT1R overexpression, or pressure overload that correlates with more advanced heart failure phenotypes. This was not associated with increased PKA enzymatic activity, suggesting potential deficits in phosphatase activity at PKA-regulated phospho-sites. Taken together, this study suggests Rac1\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylation dampens adrenergic drive and PKA-dependent modulation of the phospho-proteome in response to cardiovascular stress, revealing essential functions for\n                    <jats:italic>S<\/jats:italic>\n                    -acylated Rac1 in cardiac adaptation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.193733","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T16:00:23Z","timestamp":1757433623000},"source":"Crossref","is-referenced-by-count":8,"title":["Rac1 palmitoylation is required for cardiac stress adaptation and regulation of protein kinase A signaling"],"prefix":"10.1172","volume":"10","author":[{"given":"James P.","family":"Teuber","sequence":"first","affiliation":[{"name":"Department of Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel 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