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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- 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.
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- Chromosomes and Gene Expression
- Evolutionary Biology
Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of regulatory DNA, and also create new regulatory DNA, a process called regulatory emergence. Non-regulatory and regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires a stretch of DNA called a promoter, which contains two motifs called –10 and –35 boxes. However, these motifs may occur in both promoters and non-promoter DNA in multiple copies. They have been implicated in some studies to improve promoter activity, and in others to repress it. Here, we ask whether the presence of such motifs in different genetic sequences influences promoter evolution and emergence. To understand whether and how promoter motifs influence promoter emergence and evolution, we start from 50 ‘promoter islands’, DNA sequences enriched with –10 and –35 boxes. We mutagenize these starting ‘parent’ sequences, and measure gene expression driven by 240,000 of the resulting mutants. We find that the probability that mutations create an active promoter varies more than 200-fold, and is not correlated with the number of promoter motifs. For parent sequences without promoter activity, mutations created over 1500 new –10 and –35 boxes at unique positions in the library, but only ~0.3% of these resulted in de-novo promoter activity. Only ~13% of all –10 and –35 boxes contribute to de-novo promoter activity. For parent sequences with promoter activity, mutations created new –10 and –35 boxes in 11 specific positions that partially overlap with preexisting ones to modulate expression. We also find that –10 and –35 boxes do not repress promoter activity. Overall, our work demonstrates how promoter motifs influence promoter emergence and evolution. It has implications for predicting and understanding regulatory evolution, de novo genes, and phenotypic evolution.
