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.
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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Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here, we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Although gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.
