Reduced Myocardial Creatine Kinase Flux in Human Myocardial Infarction

Bottomley, Paul A.; Wu, Kathérine C.; Gerstenblith, Gary; Schulman, Steven P.; Steinberg, Angela; Weiss, Robert G.

doi:10.1161/circulationaha.108.823187

Cited by 70 publications

(59 citation statements)

References 39 publications

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“…S3A). Even though this is a statistically significant reduction, the energetic reserves are still quite considerable [pathologic conditions are associated with 40-50% decreases in PCr (20)(21)(22)]. There was no significant difference in ATP content (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…LC 20 Phosphorylation. LC 20 phosphorylation was determined as described previously (39-42) (SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, skinned tissue strips were denatured, washed, and dried. LC 20 was solubilized in PAGE sample buffer, resolved on a polyacrylamide gel, and transferred to a nitrocellulose membrane. Phosphorylated and unphosphorylated LC 20 were identified by immunoblotting using a LC 20 mAb (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Because myosin light chain (LC 20 ) phosphorylation regulates smooth muscle cross-bridge cycling, we quantified the level of phosphorylation in smooth muscle preparations with solutions containing ATP vs. dATP. For ATP, LC 20 phosphorylation was 2 ± 0.5% at rest [negative logarithm of calcium ion concentration (pCa) 9] and increased to 33 ± 2% at pCa 4 (n = 3), whereas for dATP, LC 20 phosphorylation increased from 3 ± 1% to 34 ± 5% (n = 3). Because LC 20 phosphorylation did not differ between preparations with ATP vs. dATP, these data suggest that dATP does not alter the regulation of smooth muscle.…”

Section: S2bmentioning

confidence: 99%

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Transgenic overexpression of ribonucleotide reductase improves cardiac performance

Nowakowski

Kolwicz

Korte

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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.metabolism | inotropy | cross-bridge cycling A wide variety of cardiac pathologies such as myocardial infarct, dilated cardiomyopathy, and congestive heart failure involve reduced systolic function of ventricles that often results from altered ATP-mediated actin-myosin (cross-bridge) cycling (1-4). The schematic shown in Fig. 1 outlines the basic components of this chemomechanical cycle that are critical to understand how cardiomyocytes use energy to develop tension and shortening: (i) ATP bound to detached myosin is hydrolyzed to ADP and inorganic phosphate (Pi); (ii) myosin binds to actin and undergoes the power-stroke associated with Pi release, tension development, and shortening; (iii) ADP is released from myosin; and (iv) ATP binds and precipitates myosin detachment from actin.We (5-8) and others (9-17) have reported that striated muscle myosin can use most naturally occurring nucleotides to support cross-bridge cycling and contraction to varying degrees. Although most are not as effective as ATP, we found that 2-deoxy-ATP (dATP) is more effective than ATP as a substrate for contraction of demembranated cardiac muscle, augmenting both force and shortening at all levels of Ca 2+ -mediated contractile activation (5-8). Our detailed biochemical and mechanical analysis suggests that dATP increases the rates of both myosin binding and product release (steps 2 and 3 in Fig. 1) (6). More recently, we reported that adenoviral overexpres...

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Section: Resultsmentioning

confidence: 97%

“…LC 20 Phosphorylation. LC 20 phosphorylation was determined as described previously (39-42) (SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: S2bmentioning

confidence: 99%

See 2 more Smart Citations

Transgenic overexpression of ribonucleotide reductase improves cardiac performance

Nowakowski

Kolwicz

Korte

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Since the accumulated P-GAA levels are generally high in GAMT knockout animals, it is likely that the relatively mild phenotype in terms of skeletal and cardiac muscle performance can be explained by this fact. Thus, the results described above do not justify the conclusions taken by Lygate et al (2013), specifically in light of the fact that reduced PCr concentrations and PCr/ATP ratios, as well as a reduced flux through the CK reaction, have been consistently seen in human myocardial infarction (Bottomley et al 2009). Zervou et al (2016) show in an elegant study that mice over-expressing the creatine transporter (CrT), and thus displaying elevated cardiac total creatine levels, were protected against ischemia/reperfusion injury via improved energy reserves.…”

Section: Creatine In Heart Function and Liver Pathologymentioning

confidence: 87%