Declining activity of serum response factor in aging aorta in relation to aneurysm progression : Age-dependent attrition of the SRF regulon and aortopathy
(2025) In Journal of Biological Chemistry 301(4). p.1-19- Abstract
- Age is a critical determinant of arterial disease, including aneurysm formation. Here, to understand the impact of aging on the arterial transcriptome, we leveraged RNA-sequencing data to define transcripts that change with advancing age in human arteries. Among the most repressed transcripts in aged individuals were those that are relevant for actomyosin structure and organization, including both myosin light chain kinase (MYLK) and smooth muscle γ-actin (ACTG2). This was associated with a reduction of serum response factor (SRF), which controls these transcripts via defined promoter elements. To determine the consequences of isolated Srf depletion, we conditionally deleted Srf in vascular smooth muscle of young mice (i8-SRF-KO mice).... (More)
- Age is a critical determinant of arterial disease, including aneurysm formation. Here, to understand the impact of aging on the arterial transcriptome, we leveraged RNA-sequencing data to define transcripts that change with advancing age in human arteries. Among the most repressed transcripts in aged individuals were those that are relevant for actomyosin structure and organization, including both myosin light chain kinase (MYLK) and smooth muscle γ-actin (ACTG2). This was associated with a reduction of serum response factor (SRF), which controls these transcripts via defined promoter elements. To determine the consequences of isolated Srf depletion, we conditionally deleted Srf in vascular smooth muscle of young mice (i8-SRF-KO mice). This led to a reduction of the SRF regulon, including Mylk and Actg2, and impaired arterial contractility, but left endothelial-dependent dilatation unaffected. Srf-depletion also increased aortic diameter and Alcian blue staining of the aortic media, which are cardinal features of aortopathy, such as aortic aneurysmal disease. Despite this, i8-SRF-KO mice were protected from aortic lesions elicited by angiotensin II (AngII). Proteomics demonstrated that Srf-depletion mimicked a protein signature of AngII treatment involving increases of the mechanoresponsive transcriptional coactivators YAP and TAZ and reduction of the Hippo kinase Lats2. Protection from aortopathy could be overcome by changing the order of KO induction and AngII administration resulting in advanced aneurysms in both i8-SRF-KO and control mice. Our work provides important insights into the molecular underpinnings of age-dependent changes in aortic function and mechanisms of adaptation in hypertension. (Less)
- Abstract (Swedish)
- Age is a critical determinant of arterial disease, including aneurysm formation. Here, to understand the impact of aging on the arterial transcriptome, we leveraged RNA-sequencing data to define transcripts that change with advancing age in human arteries. Among the most repressed transcripts in aged
individuals were those that are relevant for actomyosin structure and organization, including both myosin light chain kinase (MYLK) and smooth muscle g-actin (ACTG2). This was associated with a reduction of serum response factor (SRF), which controls these transcripts via defined promoter elements. To determine the consequences of isolated Srf depletion, we conditionally deleted Srf in vascular smooth muscle of young mice (i8-SRF-KO mice).... (More) - Age is a critical determinant of arterial disease, including aneurysm formation. Here, to understand the impact of aging on the arterial transcriptome, we leveraged RNA-sequencing data to define transcripts that change with advancing age in human arteries. Among the most repressed transcripts in aged
individuals were those that are relevant for actomyosin structure and organization, including both myosin light chain kinase (MYLK) and smooth muscle g-actin (ACTG2). This was associated with a reduction of serum response factor (SRF), which controls these transcripts via defined promoter elements. To determine the consequences of isolated Srf depletion, we conditionally deleted Srf in vascular smooth muscle of young mice (i8-SRF-KO mice). This led to a reduction of the SRF regulon, including Mylk and Actg2, and impaired arterial contractility, but left endothelial-dependent dilatation unaffected. Srf-depletion also increased aortic diameter and Alcian blue staining of the aortic media, which are cardinal features of aortopathy, such as aortic aneurysmal disease. Despite this, i8-
SRF-KO mice were protected from aortic lesions elicited by angiotensin II (AngII). Proteomics demonstrated that Srfdepletion mimicked a protein signature of AngII treatment involving increases of the mechanoresponsive transcriptional
coactivators YAP and TAZ and reduction of the Hippo kinase Lats2. Protection from aortopathy could be overcome by changing the order of KO induction and AngII administration resulting in advanced aneurysms in both i8-SRF-KO and control mice. Our work provides important insights into the molecular underpinnings of age-dependent changes in aortic function and mechanisms of adaptation in hypertension. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/be2a458c-c594-4ac5-a7f1-ebe826788caa
- author
- Rippe, Catarina LU ; Armstrong Bastrup, Joakim ; Holmberg, Johan LU ; Kawka, Katarzyna LU ; Arévalo Martinez, Marycarmen LU ; Albinsson, Sebastian LU ; Jepps, Tom A. and Swärd, Karl LU
- organization
- alternative title
- Avtagande serumresponsfaktor aktivitet i den åldrande aortan i relation till aneurysmprogression
- publishing date
- 2025-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- angiotensin II; bioinformatics; cardiovascular disease; cytoskeleton; gene knockout; hypertension; leiomodin; myocardin; myosin light chain kinase; smooth muscle γ-actin
- in
- Journal of Biological Chemistry
- volume
- 301
- issue
- 4
- article number
- 108400
- pages
- 1 - 19
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:40081573
- scopus:105001709926
- ISSN
- 1083-351X
- DOI
- 10.1016/j.jbc.2025.108400
- language
- English
- LU publication?
- yes
- id
- be2a458c-c594-4ac5-a7f1-ebe826788caa
- date added to LUP
- 2025-08-27 11:25:57
- date last changed
- 2025-08-28 04:00:51
@article{be2a458c-c594-4ac5-a7f1-ebe826788caa,
abstract = {{Age is a critical determinant of arterial disease, including aneurysm formation. Here, to understand the impact of aging on the arterial transcriptome, we leveraged RNA-sequencing data to define transcripts that change with advancing age in human arteries. Among the most repressed transcripts in aged individuals were those that are relevant for actomyosin structure and organization, including both myosin light chain kinase (MYLK) and smooth muscle γ-actin (ACTG2). This was associated with a reduction of serum response factor (SRF), which controls these transcripts via defined promoter elements. To determine the consequences of isolated Srf depletion, we conditionally deleted Srf in vascular smooth muscle of young mice (i8-SRF-KO mice). This led to a reduction of the SRF regulon, including Mylk and Actg2, and impaired arterial contractility, but left endothelial-dependent dilatation unaffected. Srf-depletion also increased aortic diameter and Alcian blue staining of the aortic media, which are cardinal features of aortopathy, such as aortic aneurysmal disease. Despite this, i8-SRF-KO mice were protected from aortic lesions elicited by angiotensin II (AngII). Proteomics demonstrated that Srf-depletion mimicked a protein signature of AngII treatment involving increases of the mechanoresponsive transcriptional coactivators YAP and TAZ and reduction of the Hippo kinase Lats2. Protection from aortopathy could be overcome by changing the order of KO induction and AngII administration resulting in advanced aneurysms in both i8-SRF-KO and control mice. Our work provides important insights into the molecular underpinnings of age-dependent changes in aortic function and mechanisms of adaptation in hypertension.}},
author = {{Rippe, Catarina and Armstrong Bastrup, Joakim and Holmberg, Johan and Kawka, Katarzyna and Arévalo Martinez, Marycarmen and Albinsson, Sebastian and Jepps, Tom A. and Swärd, Karl}},
issn = {{1083-351X}},
keywords = {{angiotensin II; bioinformatics; cardiovascular disease; cytoskeleton; gene knockout; hypertension; leiomodin; myocardin; myosin light chain kinase; smooth muscle γ-actin}},
language = {{eng}},
number = {{4}},
pages = {{1--19}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Declining activity of serum response factor in aging aorta in relation to aneurysm progression : Age-dependent attrition of the SRF regulon and aortopathy}},
url = {{http://dx.doi.org/10.1016/j.jbc.2025.108400}},
doi = {{10.1016/j.jbc.2025.108400}},
volume = {{301}},
year = {{2025}},
}