{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:03:25Z","timestamp":1775279005145,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Familial thoracic aortic aneurysm and dissection (FTAAD), caused by the pathogenic Myh11 K1256del variant, is characterized by impaired aortic contractility; however, how reduced contractility predisposes the aorta to dissection remains incompletely understood. In this study, we performed a data-driven trans-omic upstream analysis using Genome Enhancer to identify key regulatory mechanisms in aortas from Myh11 K1256del mice under baseline conditions, without exposure to exogenous pathological stimuli. Transcriptome analysis revealed enrichment of genes related to smooth muscle contraction and regulation of myosin light chain phosphatase activity. Upstream computational analysis of regulatory regions identified nuclear factor of activated T cells 1 and lymphoid enhancer-binding factor 1 as major transcription factors, and further highlighted Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) as a predicted central regulator of the dysregulated transcriptional network. Druggability analysis suggested ROCK1 and the JunB proto-oncogene AP-1 transcription factor subunit as potential therapeutic targets. Furthermore, it predicted 51 candidate therapeutants, including atorvastatin, GSK-269962A, and atovaquone. These findings indicate that even in the absence of overt pathological stimulation, aortic tissue carrying the Myh11 K1256del variant exhibits a transcriptional program centered on ROCK signaling, which may prime the aorta for maladaptive responses to additional stress and may enhance susceptibility to dissection. This computational analysis requires experimental validation, but may provide a hypothesis-generating framework for development of preventive pharmacological interventions against FTAAD.<\/jats:p>","DOI":"10.3390\/ijms27073195","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T16:34:08Z","timestamp":1774974848000},"page":"3195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Pathogenic ROCK-Signaling Network Involving a Lysine Deletion in Myh11 Renders Carriers Susceptible to Aortic Dissection"],"prefix":"10.3390","volume":"27","author":[{"given":"Hironori","family":"Okuhata","sequence":"first","affiliation":[{"name":"Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan"},{"name":"School of Medicine, Faculty of Medicine, Gunma University, Maebashi 371-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shota","family":"Tomida","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan"},{"name":"School of Medicine, Faculty of Medicine, Gunma University, Maebashi 371-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2309-265X","authenticated-orcid":false,"given":"Tamaki","family":"Ishima","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryozo","family":"Nagai","sequence":"additional","affiliation":[{"name":"Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Aizawa","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan"},{"name":"Clinical Pharmacology Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1161\/01.CIR.92.6.1376","article-title":"Acute Aortic Dissection and Its Variants","volume":"92","author":"DeSanctis","year":"1995","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.athoracsur.2006.04.098","article-title":"Familial Thoracic Aortic Aneurysms and Dissections\u2014Incidence, Modes of Inheritance, and Phenotypic Patterns","volume":"82","author":"Albornoz","year":"2006","journal-title":"Ann. 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