Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells
- University of Helsinki, Finland
Abstract
Aging, obesity, hypertension and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing and bioinformatic methods to investigate the common effects of CVD risk factors in mouse cardiac endothelial cells (ECs). Aging, obesity and pressure overload all upregulated pathways related to TGF-b signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis and cellular senescence, whereas exercise training attenuated most of the same pathways. We identified collagen chaperone Serpinh1 (also called as Hsp47) to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that increased SERPINH1 in human ECs induced mesenchymal properties, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs inducing inflammatory, senescence and mesenchymal features. SERPINH1 was identified as a potential therapeutic target in ECs.
Data availability
All RNA sequencing data have been deposited in GEO under accession code GSE145263.
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RNA sequencing of cardiac endothelial cells from the cardiovascular disease risk factor mouse modelsNCBI Gene Expression Omnibus, GSE145263.
Article and author information
Author details
Karthik Amudhala Hemanthakumar
Funding
Jenny ja Antti Wihurin Rahasto
- Karthik Amudhala Hemanthakumar
- Riikka Kivelä
Academy of Finland (297245)
- Riikka Kivelä
Sydäntutkimussäätiö
- Karthik Amudhala Hemanthakumar
- Riikka Kivelä
Sigrid Juséliuksen Säätiö
- Riikka Kivelä
Suomen Kulttuurirahasto
- Riikka Kivelä
Suomen Lääketieteen Säätiö
- Mikko I Mäyränpää
Biomedicum Helsinki-säätiö
- Karthik Amudhala Hemanthakumar
Aarne Koskelon Säätiö
- Karthik Amudhala Hemanthakumar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by the committee appointed by the District of Southern Finland (permit number ESAVI/22658/2018). The study was performed in accordance with the recommendations of FELASA. All of the animals were handled according to approved institutional animal care and use committee of the University of Helsinki. All surgery was performed under anesthesia advised by the University's veterinarians, and every effort was made to minimize suffering.
Human subjects: Human heart samples were obtained from 4 organ donor hearts, which could not be used for transplantation e.g. due to size or tissue-type mismatch. The collection was approved by institutional ethics committee and The National Authority for Medicolegal Affairs.
Reviewing Editor
- Victoria L Bautch, University of North Carolina, Chapel Hill, United States
Version history
- Received: September 2, 2020
- Accepted: March 3, 2021
- Accepted Manuscript published: March 4, 2021 (version 1)
- Version of Record published: April 13, 2021 (version 2)
Copyright
© 2021, Hemanthakumar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells
eLife 10:e62678.
https://doi.org/10.7554/eLife.62678
Further reading
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- Chromosomes and Gene Expression
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- Chromosomes and Gene Expression
Chromatin accessibility is modulated in a variety of ways to create open and closed chromatin states, both of which are critical for eukaryotic gene regulation. At the single molecule level, how accessibility is regulated of the chromatin fiber composed of canonical or variant nucleosomes is a fundamental question in the field. Here, we developed a single-molecule tracking method where we could analyze thousands of canonical H3 and centromeric variant nucleosomes imaged by high-speed atomic force microscopy. This approach allowed us to investigate how changes in nucleosome dynamics in vitro inform us about transcriptional potential in vivo. By high-speed atomic force microscopy, we tracked chromatin dynamics in real time and determined the mean square displacement and diffusion constant for the variant centromeric CENP-A nucleosome. Furthermore, we found that an essential kinetochore protein CENP-C reduces the diffusion constant and mobility of centromeric nucleosomes along the chromatin fiber. We subsequently interrogated how CENP-C modulates CENP-A chromatin dynamics in vivo. Overexpressing CENP-C resulted in reduced centromeric transcription and impaired loading of new CENP-A molecules. From these data, we speculate that factors altering nucleosome mobility in vitro, also correspondingly alter transcription in vivo. Subsequently, we propose a model in which variant nucleosomes encode their own diffusion kinetics and mobility, and where binding partners can suppress or enhance nucleosome mobility.
