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Role of smooth muscle YAP and TAZ in protection against phenotypic modulation, inflammation, and aneurysm development

Daoud, Fatima LU ; Arévalo Martínez, Marycarmen LU ; Holst, Jan LU ; Holmberg, Johan LU ; Albinsson, Sebastian LU and Swärd, Karl LU (2022) In Biochemical Pharmacology 206.
Abstract

A ruptured arterial aneurysm, especially in the aorta, represents one of the most acute and mortal conditions encountered in clinical medicine. Population-based screening in elderly men, treatment of risk factors, such as hypertension, and endovascular or open repair of rupture-prone lesions, represent cornerstones in management. Surgical repair has a sizeable effect on life-expectancy, but medical therapy that retards aneurysm growth still represents a considerable and unmet clinical need. In the current review we survey recent findings implicating the mechano-responsive transcriptional co-activators YAP and TAZ in protection from aneurysm development. Arteries from mouse mutants that lack YAP and TAZ in vascular smooth muscle respond... (More)

A ruptured arterial aneurysm, especially in the aorta, represents one of the most acute and mortal conditions encountered in clinical medicine. Population-based screening in elderly men, treatment of risk factors, such as hypertension, and endovascular or open repair of rupture-prone lesions, represent cornerstones in management. Surgical repair has a sizeable effect on life-expectancy, but medical therapy that retards aneurysm growth still represents a considerable and unmet clinical need. In the current review we survey recent findings implicating the mechano-responsive transcriptional co-activators YAP and TAZ in protection from aneurysm development. Arteries from mouse mutants that lack YAP and TAZ in vascular smooth muscle respond inadequately to mechanical stimulation, and they develop aneurysms characterized by elastin fragmentation, proteoglycan infiltration, and severe inflammation at breathtaking speed. This seems to be due, at least in part, to unscheduled activation of STING (stimulator of interferon genes), an arm of innate immunity that responds to double-stranded DNA in the cytoplasm. YAP and TAZ protect from STING activation by securing nuclear integrity. These novel insights suggest unanticipated medical therapies for sporadic and genetic aneurysms alike, involving inhibition of kinases in the Hippo pathway using small molecules, or inhibition of STING signaling itself. Translation of these novel findings into clinical therapies now represents an important priority.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cardiovascular disease, cGAMP, cGAS, Contraction, Dilatation, Myocardial infarction, MYOCD, WWTR1, YAP1
in
Biochemical Pharmacology
volume
206
article number
115307
publisher
Elsevier
external identifiers
  • pmid:36270325
  • scopus:85140299558
ISSN
0006-2952
DOI
10.1016/j.bcp.2022.115307
language
English
LU publication?
yes
id
8bc8ca4b-db75-42ad-840d-26c6e1a9271d
date added to LUP
2022-12-06 15:28:08
date last changed
2024-06-27 22:35:32
@article{8bc8ca4b-db75-42ad-840d-26c6e1a9271d,
  abstract     = {{<p>A ruptured arterial aneurysm, especially in the aorta, represents one of the most acute and mortal conditions encountered in clinical medicine. Population-based screening in elderly men, treatment of risk factors, such as hypertension, and endovascular or open repair of rupture-prone lesions, represent cornerstones in management. Surgical repair has a sizeable effect on life-expectancy, but medical therapy that retards aneurysm growth still represents a considerable and unmet clinical need. In the current review we survey recent findings implicating the mechano-responsive transcriptional co-activators YAP and TAZ in protection from aneurysm development. Arteries from mouse mutants that lack YAP and TAZ in vascular smooth muscle respond inadequately to mechanical stimulation, and they develop aneurysms characterized by elastin fragmentation, proteoglycan infiltration, and severe inflammation at breathtaking speed. This seems to be due, at least in part, to unscheduled activation of STING (stimulator of interferon genes), an arm of innate immunity that responds to double-stranded DNA in the cytoplasm. YAP and TAZ protect from STING activation by securing nuclear integrity. These novel insights suggest unanticipated medical therapies for sporadic and genetic aneurysms alike, involving inhibition of kinases in the Hippo pathway using small molecules, or inhibition of STING signaling itself. Translation of these novel findings into clinical therapies now represents an important priority.</p>}},
  author       = {{Daoud, Fatima and Arévalo Martínez, Marycarmen and Holst, Jan and Holmberg, Johan and Albinsson, Sebastian and Swärd, Karl}},
  issn         = {{0006-2952}},
  keywords     = {{Cardiovascular disease; cGAMP; cGAS; Contraction; Dilatation; Myocardial infarction; MYOCD; WWTR1; YAP1}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Biochemical Pharmacology}},
  title        = {{Role of smooth muscle YAP and TAZ in protection against phenotypic modulation, inflammation, and aneurysm development}},
  url          = {{http://dx.doi.org/10.1016/j.bcp.2022.115307}},
  doi          = {{10.1016/j.bcp.2022.115307}},
  volume       = {{206}},
  year         = {{2022}},
}