A remarkable adaptive paradigm of heart performance and protection emerges in response to the constitutive challenge of marked cardiac-specific overexpression of adenylyl cyclase type 8

Abstract

Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation 'circuity' that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.

Data availability

RNASEQ raw data have been deposited in GEO under accession code GSE205234Proteome raw data submitted to MassIVE MSV000089554

The following data sets were generated

Article and author information

Author details

  1. Kirill V Tarasov

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7799-4670
  2. Khalid Chakir

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Daniel R Riordon

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexey Lyashkov

    Translational Gerontology Branch, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ismayil Ahmet

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Maria Grazia Perino

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Allwin Jennifa Silvester

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jing Zhang

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mingyi Wang

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Yevgeniya O Lukyanenko

    Translational Gerontology Branch, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jia-Hua Qu

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Miguel Calvo-Rubio Barrera

    Translational Gerontology Branch, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Magdalena Juhaszova

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Yelena S Tarasova

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Bruce Ziman

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Richard Telljohann

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Vikas Kumar

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Mark Ranek

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. John Lammons

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Rostislav Bychkov

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Rafael de Cabo

    Translational Gerontology Branch, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2830-5693
  22. Seungho Jun

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Gizem Keceli

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9562-7994
  24. Ashish Gupta

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Dongmei Yang

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  26. Miguel A Aon

    Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  27. Luigi Adamo

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  28. Christopher H Morrell

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Walter Otu

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Cameron Carroll

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  31. Shane Chambers

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  32. Nazareno Paolocci

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  33. Thanh Huynh

    Section on medical neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  34. Karel Pacak

    Section on medical neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  35. Robert Weiss

    Department of Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  36. Loren Field

    Kraennert Institute of Cardiology, Indiana University, Idianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  37. Steven J Sollott

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  38. Edward G Lakatta

    Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, United States
    For correspondence
    lakattae@grc.nia.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4772-0035

Funding

National Heart, Lung, and Blood Institute (1R01HL155218)

  • Loren Field

National Heart, Lung, and Blood Institute (R01 HL136918,R01 HL1155760)

  • Nazareno Paolocci

National Heart, Lung, and Blood Institute (HL63030,HL61912)

  • Robert Weiss

American Heart Association (#18CDA34110140,#20TPA35500008)

  • Mark Ranek

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 studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication no. 85-23, revised 1996). The experimental protocols were approved by the Animal Care and Use Committee of the National Institutes of Health (protocol #441-LCS-2019)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Kirill V Tarasov
  2. Khalid Chakir
  3. Daniel R Riordon
  4. Alexey Lyashkov
  5. Ismayil Ahmet
  6. Maria Grazia Perino
  7. Allwin Jennifa Silvester
  8. Jing Zhang
  9. Mingyi Wang
  10. Yevgeniya O Lukyanenko
  11. Jia-Hua Qu
  12. Miguel Calvo-Rubio Barrera
  13. Magdalena Juhaszova
  14. Yelena S Tarasova
  15. Bruce Ziman
  16. Richard Telljohann
  17. Vikas Kumar
  18. Mark Ranek
  19. John Lammons
  20. Rostislav Bychkov
  21. Rafael de Cabo
  22. Seungho Jun
  23. Gizem Keceli
  24. Ashish Gupta
  25. Dongmei Yang
  26. Miguel A Aon
  27. Luigi Adamo
  28. Christopher H Morrell
  29. Walter Otu
  30. Cameron Carroll
  31. Shane Chambers
  32. Nazareno Paolocci
  33. Thanh Huynh
  34. Karel Pacak
  35. Robert Weiss
  36. Loren Field
  37. Steven J Sollott
  38. Edward G Lakatta
(2022)
A remarkable adaptive paradigm of heart performance and protection emerges in response to the constitutive challenge of marked cardiac-specific overexpression of adenylyl cyclase type 8
eLife 11:e80949.
https://doi.org/10.7554/eLife.80949

Share this article

https://doi.org/10.7554/eLife.80949

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