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
- National Institute on Aging, United States
- Johns Hopkins University, United States
- National Institute on Aging, NIH, United States
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States
- Indiana University, United States
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
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RNA-Seq Analyses of TGAC8 and WT mouse Left VentriclesNCBI Gene Expression Omnibus, GSE205234.
Article and author information
Author details
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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