Zhou Zhen, Hughes Kgosi, Saif Nisha, Kim Hyoseon, Massett Michael P, Zheng Mingjie, Cecchi Alana C, Guo Dongchuan, Murdock David R, Pan Ping, Clinton Jelita S, Wang Jun, Greally John M, Milewicz Dianna M
Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, United States of America.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
PLoS Genet. 2025 Jul 14;21(7):e1011394. doi: 10.1371/journal.pgen.1011394. eCollection 2025 Jul.
Smooth muscle cell-specific myosin heavy chain, encoded by MYH11, is selectively expressed in smooth muscle cells (SMCs). Pathogenic variants in MYH11 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 MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11E1892D/E1892D mice. Wild-type (WT) and mutant mice underwent cardiovascular phenotyping with and without transverse aortic constriction (TAC). Myh11E1892D/E1892D 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. The hypertension induced by TAC was similarly in Myh11E1892D/E1892D and WT mice, but mutant mice showed augmented ascending aortic enlargement and increased elastic fiber fragmentation on histology. Unexpectedly, male Myh11E1892D/E1892D mice undergoing 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 phenotypic heterogeneity associated with MYH11 rare variants. Given that MYH11 is selectively expressed in SMCs, these results implicate a role of SMCs in the arteries of the heart contributing to cardiac hypertrophy and failure with pressure overload.
由MYH11编码的平滑肌细胞特异性肌球蛋白重链在平滑肌细胞（SMC）中选择性表达。MYH11中的致病变异易患多种疾病，包括与动脉导管未闭相关的遗传性胸主动脉疾病、内脏肌病和巨膀胱-微结肠-肠道蠕动功能减退综合征。整个基因中存在意义不确定的罕见变异，包括MYH11 p.Glu1892Asp，我们试图确定该变异是否会在小鼠中导致胸主动脉疾病。使用基因组编辑技术生成Myh11E1892D/E1892D小鼠。野生型（WT）和突变小鼠在有或没有横向主动脉缩窄（TAC）的情况下进行心血管表型分析。Myh11E1892D/E1892D和WT小鼠在13个月龄时表现出相似的生长、血压、主动脉根部和升主动脉直径以及心脏功能，在肌电图测试中收缩和舒张情况也相似。TAC诱导的高血压在Myh11E1892D/E1892D和WT小鼠中相似，但突变小鼠在组织学上显示升主动脉扩张增加和弹性纤维断裂增加。出乎意料的是，与同样接受治疗的雄性WT小鼠相比，接受TAC的雄性Myh11E1892D/E1892D小鼠的射血分数、每搏输出量、缩短分数和心输出量降低。重要的是，左心室质量显著增加，主要是由于后壁增厚，心脏组织学证实心肌细胞肥大以及心肌和周围动脉中胶原沉积增加。这些结果进一步突出了与MYH11罕见变异相关的表型异质性。鉴于MYH11在SMC中选择性表达，这些结果表明SMC在心脏动脉中对压力过载导致的心肌肥大和心力衰竭起作用。
