Genetic approaches to identify pathological limitations in aortic smooth muscle contraction

Jian Huang, Ning Gao, Shanzhi Wang, Dianna M. Milewicz, Kristine E. Kamm, James T. Stull

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 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.

Original languageEnglish (US)
Article numbere0193769
JournalPLoS One
Volume13
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

muscle contraction
Muscle Contraction
smooth muscle
Smooth Muscle
Muscle
Smooth Muscle Myosins
Aortic Diseases
Tissue
Mutation
Phosphorylation
Myosin Heavy Chains
Myosins
myosin
mutation
Alleles
myosin heavy chains
Thoracic Diseases
chest
Myosin-Light-Chain Kinase
Myosin Light Chains

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Genetic approaches to identify pathological limitations in aortic smooth muscle contraction. / Huang, Jian; Gao, Ning; Wang, Shanzhi; Milewicz, Dianna M.; Kamm, Kristine E.; Stull, James T.

In: PLoS One, Vol. 13, No. 3, e0193769, 01.03.2018.

Research output: Contribution to journalArticle

Huang, Jian ; Gao, Ning ; Wang, Shanzhi ; Milewicz, Dianna M. ; Kamm, Kristine E. ; Stull, James T. / Genetic approaches to identify pathological limitations in aortic smooth muscle contraction. In: PLoS One. 2018 ; Vol. 13, No. 3.
@article{5011843cc13843beaffd9adf516a9432,
title = "Genetic approaches to identify pathological limitations in aortic smooth muscle contraction",
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 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.",
author = "Jian Huang and Ning Gao and Shanzhi Wang and Milewicz, {Dianna M.} and Kamm, {Kristine E.} and Stull, {James T.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1371/journal.pone.0193769",
language = "English (US)",
volume = "13",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Genetic approaches to identify pathological limitations in aortic smooth muscle contraction

AU - Huang, Jian

AU - Gao, Ning

AU - Wang, Shanzhi

AU - Milewicz, Dianna M.

AU - Kamm, Kristine E.

AU - Stull, James T.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85042702305&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042702305&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0193769

DO - 10.1371/journal.pone.0193769

M3 - Article

C2 - 29494672

AN - SCOPUS:85042702305

VL - 13

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e0193769

ER -