{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:26:36Z","timestamp":1790774796029,"version":"4.1.0"},"posted":{"date-parts":[[2024,8,16]]},"group-title":"Genetics","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T00:00:00Z","timestamp":1723766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Smooth muscle cell-specific myosin heavy chain, encoded by\n                  <jats:italic>MYH11<\/jats:italic>\n                  , is selectively expressed in smooth muscle cells (\n                  <jats:bold>SMC<\/jats:bold>\n                  s). Pathogenic variants in\n                  <jats:italic>MYH11<\/jats:italic>\n                  predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including\n                  <jats:italic>MYH11<\/jats:italic>\n                  p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate\n                  <jats:italic>Myh11<\/jats:italic>\n                  <jats:sup>E1892D\/E1892D<\/jats:sup>\n                  mice. Wild-type (\n                  <jats:bold>WT<\/jats:bold>\n                  ) and mutant mice underwent cardiovascular phenotyping and with transverse aortic constriction (\n                  <jats:bold>TAC<\/jats:bold>\n                  ).\n                  <jats:italic>Myh11<\/jats:italic>\n                  <jats:sup>E1892D\/E1892D<\/jats:sup>\n                  and WT mice displayed similar growth, blood pressure, root and ascending aortic diameters, and cardiac function up to 13 months of age, along with similar contraction and relaxation on myographic testing. TAC induced hypertension similarly in\n                  <jats:italic>Myh11<\/jats:italic>\n                  <jats:sup>E1892D\/E1892D<\/jats:sup>\n                  and WT mice, but mutant mice showed augmented ascending aortic enlargement and increased elastic fragmentation on histology. Unexpectedly, male\n                  <jats:italic>Myh11<\/jats:italic>\n                  <jats:sup>E1892D\/E1892D<\/jats:sup>\n                  mice two weeks post-TAC had decreased ejection fraction, stroke volume, fractional shortening, and cardiac output compared to similarly treated male WT mice. Importantly, left ventricular mass increased significantly due to primarily posterior wall thickening, and cardiac histology confirmed cardiomyocyte hypertrophy and increased collagen deposition in the myocardium and surrounding arteries. These results further highlight the clinical heterogeneity associated with\n                  <jats:italic>MYH11<\/jats:italic>\n                  rare variants. Given that\n                  <jats:italic>MYH11<\/jats:italic>\n                  is selectively expressed in SMCs, these results implicate a role of vascular SMCs in the heart contributing to cardiac hypertrophy and failure with pressure overload.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>\n                    In this study, we explore the impact of a specific genetic variant,\n                    <jats:italic>MYH11<\/jats:italic>\n                    p.Glu1892Asp, on the heart and blood vessels in mice. The\n                    <jats:italic>MYH11<\/jats:italic>\n                    gene is crucial for smooth muscle cells, which are found in the walls of blood vessels and play an important role in various vascular diseases. We created mice with this genetic variant to see if it would lead to thoracic aortic disease, a condition affecting the main artery from the heart. We found that mice with the variant were similar to normal mice in many aspects, such as growth, blood pressure, and heart function, for up to 13 months. However, when we induced high blood pressure in the mice, the mutant mice showed more significant enlargement of the aorta and damage to the elastic fibers in the aortic walls. Interestingly, male mutant mice also developed heart problems, such as reduced heart pumping ability and increased heart muscle thickness, after the high blood pressure challenge. This was accompanied by signs of heart muscle cell enlargement and increased tissue stiffness. These findings suggest that this rare\n                    <jats:italic>MYH11<\/jats:italic>\n                    variant can contribute to a range of heart and vascular issues, particularly under conditions of pressure overload, and highlight the importance of smooth muscle cells in the development of these problems.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.15.608063","type":"posted-content","created":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T00:20:10Z","timestamp":1723854010000},"source":"Crossref","is-referenced-by-count":4,"title":["<i>MYH11<\/i>\n                  rare variant augments aortic growth and induces cardiac hypertrophy and heart failure with pressure overload"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7880-5998","authenticated-orcid":false,"given":"Zhen","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kgosi","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2868-0584","authenticated-orcid":false,"given":"Nisha","family":"Saif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8933-6042","authenticated-orcid":false,"given":"Hyoseon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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