Genetic approaches to identify pathological limitations in aortic smooth muscle contraction

PloS One
Jian HuangJames T Stull

Abstract

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...Continue Reading

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Citations

Oct 21, 2020·PLoS Computational Biology·M Latorre, J D Humphrey
Dec 4, 2020·Nature·Shixin YangRoger Craig

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Methods Mentioned

BETA
dissections
transgenic
force measurements
electrophoresis
biosensor

Software Mentioned

GraphPad Prism
ImageQuant
ImageQuantTL

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