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.

The following data sets were generated

Article and author information

Author details

  1. Karthik Amudhala Hemanthakumar

    Faculty of Medicine, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6151-1005
  2. Shentong Fang

    Faculty of Medicine, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3520-7007
  3. Andrey Anisimov

    Faculty of Medicine, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0259-1273
  4. Mikko I Mäyränpää

    Pathology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  5. Eero Mervaala

    Faculty of Medicine, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  6. Riikka Kivelä

    Faculty of Medicine, University of Helsinki, Helsinki, Finland
    For correspondence
    riikka.kivela@helsinki.fi
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2686-8890

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.

Reviewing Editor

  1. Victoria L Bautch, University of North Carolina, Chapel Hill, United States

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.

Version history

  1. Received: September 2, 2020
  2. Accepted: March 3, 2021
  3. Accepted Manuscript published: March 4, 2021 (version 1)
  4. 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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  1. Karthik Amudhala Hemanthakumar
  2. Shentong Fang
  3. Andrey Anisimov
  4. Mikko I Mäyränpää
  5. Eero Mervaala
  6. Riikka Kivelä
(2021)
Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells
eLife 10:e62678.
https://doi.org/10.7554/eLife.62678

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https://doi.org/10.7554/eLife.62678

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