title: Transgenic overexpression of ribonucleotide reductase improves cardiac performance.
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 (31)P 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.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Nowakowski
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kolwicz
authors.forename: Frederick Steven
authors.initials: FS
authors.lastname: Korte
authors.forename: Zhaoxiong
authors.initials: Z
authors.lastname: Luo
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Robinson-Hamm
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Page
authors.forename: Frank
authors.initials: F
authors.lastname: Brozovich
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.forename: Michael
authors.initials: M
authors.lastname: Regnier
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004452:Echocardiography; D005786:Gene Expression Regulation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D010641:Phenotype; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism; D013599:Systole; D019076:Transgenes
chemical_list: D000255:Adenosine Triphosphate; D012264:Ribonucleotide Reductases