Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX United States of America.
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX United States of America.
PLoS One. 2018 Mar 1;13(3):e0193769. doi: 10.1371/journal.pone.0193769. eCollection 2018.
Aortic smooth muscle contains limiting amounts of myosin light chain kinase (MLCK) for myosin regulatory light chain (RLC) phosphorylation and contraction that predisposes to thoracic aortic disease in humans containing heterozygous loss-of-function mutations in MYLK. We tested the hypothesis that thoracic aortic smooth muscle contraction may also be susceptible to variations in the smooth muscle-specific isoform of the motor protein myosin where inactivation of one Myh11 allele or the presence of one Myh11 missense variant associated with an increased risk of human aortic disease may result in a reduced force development response. Additionally, other kinds of smooth muscles may be less sensitive to the effects of mutations in one smooth muscle myosin allele, similar to results obtained with Mylk. Force development responses were reduced in aortic tissue from a conditional knockout of smooth muscle myosin heavy chain in adult mice (Myh11+/- or Myh11-/-) with a greater reduction with homozygous vs heterozygous tissues. Similar reductions in force responses were obtained with tissues containing either a heterozygous or homozygous knockin mutation in smooth muscle myosin heavy chain (Myh11+/R247C or Myh11R247C/R247C mutations that cause human aortic disease) with no significant changes in RLC phosphorylation. Agonist-dependent force responses were not reduced significantly in urinary bladder, ileal, or tracheal tissues from Myh11+/- mice while only ileal tissue showed a reduced force response in Myh11R247C/R247C mice. Thus, heterozygous mutations in Myh11 associated with reduced myosin function result in compromised contractile function primarily in aortic smooth muscle.
主动脉平滑肌中的肌球蛋白轻链激酶（MLCK）含量有限，可将肌球蛋白调节轻链（RLC）磷酸化并引发收缩，这使得人类的胸主动脉疾病易感性增加，这些疾病包含 MYLK 的杂合功能丧失突变。我们检验了一个假说，即胸主动脉平滑肌收缩也可能易受运动蛋白肌球蛋白的平滑肌特异性同工型的变异影响，其中一个 Myh11 等位基因失活或存在与人类主动脉疾病风险增加相关的一个 Myh11 错义变异，可能导致力发展反应降低。此外，其他类型的平滑肌可能对一个平滑肌肌球蛋白等位基因的突变影响不太敏感，这与 Mylk 获得的结果类似。在成年小鼠的平滑肌肌球蛋白重链条件性敲除（Myh11+/-或 Myh11-/-）的主动脉组织中，力发展反应降低，杂合组织比纯合组织的降低更为明显。在含有平滑肌肌球蛋白重链杂合或纯合敲入突变（Myh11+/R247C 或 Myh11R247C/R247C 突变导致人类主动脉疾病）的组织中也获得了类似的力反应降低，但 RLC 磷酸化没有明显变化。在 Myh11+/-小鼠的尿膀胱、回肠或气管组织中，激动剂依赖性力反应没有明显降低，而仅在 Myh11R247C/R247C 小鼠的回肠组织中力反应降低。因此，与肌球蛋白功能降低相关的 Myh11 杂合突变导致主要在主动脉平滑肌中收缩功能受损。
