A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8
Author:
Tarasov Kirill V1ORCID, Chakir Khalid1, Riordon Daniel R1, Lyashkov Alexey E2, Ahmet Ismayil1, Perino Maria Grazia1, Silvester Allwin Jennifa1, Zhang Jing1, Wang Mingyi1, Lukyanenko Yevgeniya O2, Qu Jia-Hua1, Barrera Miguel Calvo-Rubio2, Juhaszova Magdalena1, Tarasova Yelena S1, Ziman Bruce1, Telljohann Richard1, Kumar Vikas1, Ranek Mark3, Lammons John1, Bychkov Rostislav1, de Cabo Rafael2ORCID, Jun Seungho3, Keceli Gizem3ORCID, Gupta Ashish3, Yang Dongmei1, Aon Miguel A1, Adamo Luigi3, Morrell Christopher H1, Otu Walter1, Carroll Cameron1, Chambers Shane1, Paolocci Nazareno3, Huynh Thanh4, Pacak Karel4, Weiss Robert3, Field Loren5, Sollott Steven J1, Lakatta Edward G1ORCID
Affiliation:
1. Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health 2. Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health 3. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine 4. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health 5. Kraennert Institute of Cardiology, Indiana University School of Medicine
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.
Funder
National Heart, Lung, and Blood Institute American Heart Association
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
15 articles.
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