Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells
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.
-
RNA sequencing of cardiac endothelial cells from the cardiovascular disease risk factor mouse modelsNCBI Gene Expression Omnibus, GSE145263.
Article and author information
Author details
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.
Metrics
-
- 3,308
- views
-
- 412
- downloads
-
- 15
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Chromosomes and Gene Expression
- Cell Biology
eLife is pleased to present a Special Issue to highlight recent advances in the mechanistic understanding of aging and interventions that extend longevity.
-
- Cancer Biology
- Chromosomes and Gene Expression
MYC family oncoproteins regulate the expression of a large number of genes and broadly stimulate elongation by RNA polymerase II (RNAPII). While the factors that control the chromatin association of MYC proteins are well understood, much less is known about how interacting proteins mediate MYC’s effects on transcription. Here, we show that TFIIIC, an architectural protein complex that controls the three-dimensional chromatin organisation at its target sites, binds directly to the amino-terminal transcriptional regulatory domain of MYCN. Surprisingly, TFIIIC has no discernible role in MYCN-dependent gene expression and transcription elongation. Instead, MYCN and TFIIIC preferentially bind to promoters with paused RNAPII and globally limit the accumulation of non-phosphorylated RNAPII at promoters. Consistent with its ubiquitous role in transcription, MYCN broadly participates in hubs of active promoters. Depletion of TFIIIC further increases MYCN localisation to these hubs. This increase correlates with a failure of the nuclear exosome and BRCA1, both of which are involved in nascent RNA degradation, to localise to active promoters. Our data suggest that MYCN and TFIIIC exert an censoring function in early transcription that limits promoter accumulation of inactive RNAPII and facilitates promoter-proximal degradation of nascent RNA.