Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1

Jon M. Florence, Agnieszka Krupa, Laela M. Booshehri, Timothy C. Allen, Anna K. Kurdowska

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The atherosclerotic process begins when vascular endothelial cells undergo pro-inflammatory changes such as aberrant activation to dysfunctional phenotypes and apoptosis, leading to loss of vascular integrity. Our laboratory has demonstrated that exposure of mice to second hand smoke triggers an increase in expression of metalloproteinase-9. Further, metalloproteinase-9 released by second hand smoke-activated leukocytes may propagate pro-atherogenic alterations in endothelial cells. We have shown that levels of metalloproteinase-9 were increased in the plasma from apolipoprotein E deficient (ApoE-/- ) mice exposed to second hand smoke relative to non-exposed controls. Moreover, we have collected data from two different, but complementary, treatments of second hand smoke exposed atherosclerotic mice. Animals received either cell specific metalloproteinase-9 directed siRNA to minimize metalloproteinase-9 expression in neutrophils and endothelial cells, or a pharmacological inhibitor of Bruton's tyrosine kinase which indirectly limits metalloproteinase-9 production in neutrophils. These treatments reduced atherosclerotic changes in mice and improved overall vascular health. We also demonstrated that metalloproteinase-9 could activate endothelial cells and induce their apoptosis via cleavage of protease activated receptor-1. In summary, better understanding of metalloproteinase-9's pathogenic capabilities as well as novel signaling pathways involved may lead to development of treatments which may provide additional benefits to atherosclerosis patients with a history of second hand smoke exposure.

Original languageEnglish (US)
Article numbere0171427
JournalPLoS One
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

PAR-1 Receptor
Metalloproteases
metalloproteinases
atherosclerosis
Atherosclerosis
proteinases
Tobacco Smoke Pollution
smoke
receptors
Smoke
Endothelial cells
hands
endothelial cells
Endothelial Cells
blood vessels
mice
Blood Vessels
neutrophils
Neutrophils
apoptosis

ASJC Scopus subject areas

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

Cite this

Florence, J. M., Krupa, A., Booshehri, L. M., Allen, T. C., & Kurdowska, A. K. (2017). Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1. PLoS One, 12(2), [e0171427]. https://doi.org/10.1371/journal.pone.0171427

Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1. / Florence, Jon M.; Krupa, Agnieszka; Booshehri, Laela M.; Allen, Timothy C.; Kurdowska, Anna K.

In: PLoS One, Vol. 12, No. 2, e0171427, 01.02.2017.

Research output: Contribution to journalArticle

Florence, Jon M. ; Krupa, Agnieszka ; Booshehri, Laela M. ; Allen, Timothy C. ; Kurdowska, Anna K. / Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1. In: PLoS One. 2017 ; Vol. 12, No. 2.
@article{cf40ec8114d140bb92933ba77419240d,
title = "Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1",
abstract = "The atherosclerotic process begins when vascular endothelial cells undergo pro-inflammatory changes such as aberrant activation to dysfunctional phenotypes and apoptosis, leading to loss of vascular integrity. Our laboratory has demonstrated that exposure of mice to second hand smoke triggers an increase in expression of metalloproteinase-9. Further, metalloproteinase-9 released by second hand smoke-activated leukocytes may propagate pro-atherogenic alterations in endothelial cells. We have shown that levels of metalloproteinase-9 were increased in the plasma from apolipoprotein E deficient (ApoE-/- ) mice exposed to second hand smoke relative to non-exposed controls. Moreover, we have collected data from two different, but complementary, treatments of second hand smoke exposed atherosclerotic mice. Animals received either cell specific metalloproteinase-9 directed siRNA to minimize metalloproteinase-9 expression in neutrophils and endothelial cells, or a pharmacological inhibitor of Bruton's tyrosine kinase which indirectly limits metalloproteinase-9 production in neutrophils. These treatments reduced atherosclerotic changes in mice and improved overall vascular health. We also demonstrated that metalloproteinase-9 could activate endothelial cells and induce their apoptosis via cleavage of protease activated receptor-1. In summary, better understanding of metalloproteinase-9's pathogenic capabilities as well as novel signaling pathways involved may lead to development of treatments which may provide additional benefits to atherosclerosis patients with a history of second hand smoke exposure.",
author = "Florence, {Jon M.} and Agnieszka Krupa and Booshehri, {Laela M.} and Allen, {Timothy C.} and Kurdowska, {Anna K.}",
year = "2017",
month = "2",
day = "1",
doi = "10.1371/journal.pone.0171427",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1

AU - Florence, Jon M.

AU - Krupa, Agnieszka

AU - Booshehri, Laela M.

AU - Allen, Timothy C.

AU - Kurdowska, Anna K.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - The atherosclerotic process begins when vascular endothelial cells undergo pro-inflammatory changes such as aberrant activation to dysfunctional phenotypes and apoptosis, leading to loss of vascular integrity. Our laboratory has demonstrated that exposure of mice to second hand smoke triggers an increase in expression of metalloproteinase-9. Further, metalloproteinase-9 released by second hand smoke-activated leukocytes may propagate pro-atherogenic alterations in endothelial cells. We have shown that levels of metalloproteinase-9 were increased in the plasma from apolipoprotein E deficient (ApoE-/- ) mice exposed to second hand smoke relative to non-exposed controls. Moreover, we have collected data from two different, but complementary, treatments of second hand smoke exposed atherosclerotic mice. Animals received either cell specific metalloproteinase-9 directed siRNA to minimize metalloproteinase-9 expression in neutrophils and endothelial cells, or a pharmacological inhibitor of Bruton's tyrosine kinase which indirectly limits metalloproteinase-9 production in neutrophils. These treatments reduced atherosclerotic changes in mice and improved overall vascular health. We also demonstrated that metalloproteinase-9 could activate endothelial cells and induce their apoptosis via cleavage of protease activated receptor-1. In summary, better understanding of metalloproteinase-9's pathogenic capabilities as well as novel signaling pathways involved may lead to development of treatments which may provide additional benefits to atherosclerosis patients with a history of second hand smoke exposure.

AB - The atherosclerotic process begins when vascular endothelial cells undergo pro-inflammatory changes such as aberrant activation to dysfunctional phenotypes and apoptosis, leading to loss of vascular integrity. Our laboratory has demonstrated that exposure of mice to second hand smoke triggers an increase in expression of metalloproteinase-9. Further, metalloproteinase-9 released by second hand smoke-activated leukocytes may propagate pro-atherogenic alterations in endothelial cells. We have shown that levels of metalloproteinase-9 were increased in the plasma from apolipoprotein E deficient (ApoE-/- ) mice exposed to second hand smoke relative to non-exposed controls. Moreover, we have collected data from two different, but complementary, treatments of second hand smoke exposed atherosclerotic mice. Animals received either cell specific metalloproteinase-9 directed siRNA to minimize metalloproteinase-9 expression in neutrophils and endothelial cells, or a pharmacological inhibitor of Bruton's tyrosine kinase which indirectly limits metalloproteinase-9 production in neutrophils. These treatments reduced atherosclerotic changes in mice and improved overall vascular health. We also demonstrated that metalloproteinase-9 could activate endothelial cells and induce their apoptosis via cleavage of protease activated receptor-1. In summary, better understanding of metalloproteinase-9's pathogenic capabilities as well as novel signaling pathways involved may lead to development of treatments which may provide additional benefits to atherosclerosis patients with a history of second hand smoke exposure.

UR - http://www.scopus.com/inward/record.url?scp=85011695802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011695802&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0171427

DO - 10.1371/journal.pone.0171427

M3 - Article

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e0171427

ER -