Transgenic overexpression of ribonucleotide reductase improves cardiac performance

Sarah G. Nowakowski, Stephen C. Kolwicz, Frederick Steven Korte, Zhaoxiong Luo, Jacqueline N. Robinson-Hamm, Jennifer L. Page, Frank Brozovich, Robert S. Weiss, Rong Tian, Charles E. Murry, Michael Regnier

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

We previously demonstrated that cardiac myosin can use 2-deoxy-ATP (dATP) as an energy substrate, that it enhances contraction and relaxation with minimal effect on calcium-handling properties in vitro, and that contractile enhancement occurs with only minor elevation of cellular [dATP]. Here, we report the effect of chronically enhanced dATP concentration on cardiac function using a transgenic mouse that overexpresses the enzyme ribonucleotide reductase (TgRR), which catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis. Hearts from TgRR mice had elevated left ventricular systolic function compared with wild-type (WT) mice, both in vivo and in vitro, without signs of hypertrophy or altered diastolic function. Isolated cardiomyocytes from TgRR mice had enhanced contraction and relaxation, with no change in Ca 2+ transients, suggesting targeted improvement of myofilament function. TgRR hearts had normal ATP and only slightly decreased phosphocreatine levels by 31P NMR spectroscopy, and they maintained rate responsiveness to dobutamine challenge. These data demonstrate long-term (at least 5-mo) elevation of cardiac [dATP] results in sustained elevation of basal left ventricular performance, with maintained β-adrenergic responsiveness and energetic reserves. Combined with results from previous studies, we conclude that this occurs primarily via enhanced myofilament activation and contraction, with similar or faster ability to relax. The data are sufficiently compelling to consider elevated cardiac [dATP] as a therapeutic option to treat systolic dysfunction.

Original languageEnglish (US)
Pages (from-to)6187-6192
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number15
DOIs
StatePublished - Apr 9 2013

Keywords

  • Cross-bridge cycling
  • Inotropy
  • Metabolism

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Transgenic overexpression of ribonucleotide reductase improves cardiac performance'. Together they form a unique fingerprint.

  • Cite this

    Nowakowski, S. G., Kolwicz, S. C., Korte, F. S., Luo, Z., Robinson-Hamm, J. N., Page, J. L., Brozovich, F., Weiss, R. S., Tian, R., Murry, C. E., & Regnier, M. (2013). Transgenic overexpression of ribonucleotide reductase improves cardiac performance. Proceedings of the National Academy of Sciences of the United States of America, 110(15), 6187-6192. https://doi.org/10.1073/pnas.1220693110