Tougas Carson L, Grindrod Tabor, Cai Lawrence X, Alkassis Fariz F, Kasahara Hideko
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, United States.
Front Physiol. 2019 Jun 6;10:696. doi: 10.3389/fphys.2019.00696. eCollection 2019.
Recent studies identified heterozygous variants in gene that encodes cardiac myosin light chain kinase (cMLCK) are related to familial dilated cardiomyopathy (DCM) for the first time. Autosomal dominant traits suggest that pathogenesis of DCM could be related to heterozygous loss-of-function variants (haploinsufficiency). We previously generated and examined homozygous knockout mice that lead to heart failure. It had yet to be examined whether heterozygous knockout mice represent a DCM-like phenotype. Heterozygous knockout ( ) mice were examined regarding cardiac function, heart histology and expression of cMLCK protein and mRNA relative to age-matched wild-type controls ( ). At 4 months of age, cardiac contractility in heterozygous knockout mice was reduced with percent fractional shortening of 23.3 ± 1.2% compared to 30.1 ± 1.8% in control ( vs. , = 9 each). In 4-month-old heterozygous knockout hearts, expression of cMLCK mRNA was expectedly reduced by almost half, however, protein expression was reduced by approximately 75% relative to the control wild-type ( vs. , = 9 each). Isolated ventricular cardiomyocytes from heterozygous knockout mice were larger with increase of short-axis length relative to the cardiomyocytes from control mice. However, increase of heart failure markers as well as interstitial fibrosis were not evident in heterozygous knockout mice compared to controls. Heterozygous knockout mice show mild reduction of cardiac contractility by 4 months of age, and proteins reduced by approximately 75% relative to the control wild-type mice. These mice partly resemble human with the heterozygous mutation, but the reduction in cardiac contractility was milder.
最近的研究首次发现，编码心肌肌球蛋白轻链激酶（cMLCK）的基因中的杂合变异与家族性扩张型心肌病（DCM）有关。常染色体显性特征表明，DCM的发病机制可能与杂合功能丧失变异（单倍剂量不足）有关。我们之前培育并检测了导致心力衰竭的纯合敲除小鼠。尚未研究杂合敲除小鼠是否表现出类似DCM的表型。相对于年龄匹配的野生型对照（ ），对杂合敲除（ ）小鼠的心脏功能、心脏组织学以及cMLCK蛋白和mRNA的表达进行了检测。在4个月大时，杂合敲除小鼠的心脏收缩力降低，分数缩短率为23.3±1.2%，而对照组为30.1±1.8%（每组 = 9只， vs. ）。在4个月大的杂合敲除心脏中，cMLCK mRNA的表达预期减少了近一半，然而，相对于对照野生型，蛋白表达减少了约75%（每组 = 9只， vs. ）。与对照小鼠的心肌细胞相比，来自杂合敲除小鼠的分离心室心肌细胞更大，短轴长度增加。然而，与对照组相比，杂合敲除小鼠中心力衰竭标志物的增加以及间质纤维化并不明显。杂合 敲除小鼠在4个月大时心脏收缩力轻度降低，相对于对照野生型小鼠，蛋白减少了约75%。这些小鼠部分类似于具有杂合 突变的人类，但心脏收缩力的降低较为轻微。
