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Articles by W Kutschke
Total Records ( 3 ) for W Kutschke
  S Wei , A Guo , B Chen , W Kutschke , Y. P Xie , K Zimmerman , R. M Weiss , M. E Anderson , H Cheng and L. S. Song

The transverse tubule (T-tubule) system is the ultrastructural substrate for excitation–contraction coupling in ventricular myocytes; T-tubule disorganization and loss are linked to decreased contractility in end stage heart failure (HF).


We sought to examine (1) whether pathological T-tubule remodeling occurs early in compensated hypertrophy and, if so, how it evolves during the transition from hypertrophy to HF; and (2) the role of junctophilin-2 in T-tubule remodeling.

Methods and Results:

We investigated T-tubule remodeling in relation to ventricular function during HF progression using state-of-the-art confocal imaging of T-tubules in intact hearts, using a thoracic aortic banding rat HF model. We developed a quantitative T-tubule power (TTpower) index to represent the integrity of T-tubule structure. We found that discrete local loss and global reorganization of the T-tubule system (leftward shift of TTpower histogram) started early in compensated hypertrophy in left ventricular (LV) myocytes, before LV dysfunction, as detected by echocardiography. With progression from compensated hypertrophy to early and late HF, T-tubule remodeling spread from the LV to the right ventricle, and TTpower histograms of both ventricles gradually shifted leftward. The mean LV TTpower showed a strong correlation with ejection fraction and heart weight to body weight ratio. Over the progression to HF, we observed a gradual reduction in the expression of a junctophilin protein (JP-2) implicated in the formation of T-tubule/sarcoplasmic reticulum junctions. Furthermore, we found that JP-2 knockdown by gene silencing reduced T-tubule structure integrity in cultured adult ventricular myocytes.


T-tubule remodeling in response to thoracic aortic banding stress begins before echocardiographically detectable LV dysfunction and progresses over the development of overt structural heart disease. LV T-tubule remodeling is closely associated with the severity of cardiac hypertrophy and predicts LV function. Thus, T-tubule remodeling may constitute a key mechanism underlying the transition from compensated hypertrophy to HF.

  S. D Hingtgen , Z Li , W Kutschke , X Tian , R. V Sharma and R. L. Davisson

Recent studies from our laboratory and others have shown that increases in cytoplasmic superoxide (O2·–) levels and Akt activation play a key role in agonist-stimulated NF-B activation and cardiomyocyte hypertrophy in vitro. In this study, we tested the hypothesis that adenovirus (Ad)-mediated intramyocardial gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD) or a dominant-negative form of Akt (AdDNAkt) in mice would attenuate pressure overload-induced increases in activation of the redox-sensitive transcription factor NF-B and cardiac hypertrophy. Adult C57BL/6 mice were subjected to thoracic aortic banding (TAB) or sham surgery, and intramyocardial injections of viral vectors (AdCu/ZnSOD, AdDNAkt, or control) were performed. There was robust transgene expression in the heart, which peaked 6–7 days after injection and then declined to undetectable levels by 12–14 days. In mice injected with AdBgL II, TAB caused a significant increase in O2·– generation and cardiac mass at 1 wk, and these responses were markedly attenuated by AdCu/ZnSOD. In addition, TAB induced time-dependent activation of NF-B in the myocardium as measured longitudinally by in vivo bioluminescent imaging of NF-B-dependent luciferase expression. This was also abolished by intracardiac AdCu/ZnSOD or AdDNAkt, but not the control vector. The inhibition of Akt and O2·–-mediated NF-B activation in TAB hearts was associated with an attenuation of cardiac hypertrophy. Since a direct cause-and-effect relationship between NF-B activation and cardiomyocyte hypertrophy has been established previously, our data support the hypothesis that increased O2·– generation and Akt activation are key signaling intermediates in pressure overload-induced activation of NF-B and cardiac hypertrophy.

  S. L Pierce , W Kutschke , R Cabeza and S. K. England

Transgenic and knockout mouse models have proven useful in the study of genes necessary for parturition—including genes that affect the timing and/or progression of labor contractions. However, taking full advantage of these models will require a detailed characterization of the contractile patterns in the mouse uterus. Currently the best methodology for this has been measurement of isometric tension in isolated muscle strips in vitro. However, this methodology does not provide a real-time measure of changes in uterine pressure over the course of pregnancy. Recent advances have opened the possibility of using radiotelemetric devices to more accurately and comprehensively study intrauterine pressure in vivo. We tested the effectiveness of this technology in the mouse, in both wild-type (WT) mice and a mouse model of defective parturition (SK3 channel-overexpressing mice), after surgical implant of telemetry transmitters into the uterine horn. Continuous recordings from day 18 of pregnancy through delivery revealed that WT mice typically deliver during the 12-h dark cycle after 19.5 days postcoitum. In these mice, intrauterine pressure gradually increases during this cycle, to threefold greater than that measured during the 12-h cycle before delivery. SK3-overexpressing mice, by contrast, exhibited lower intrauterine pressure over the same period. These results are consistent with the outcome of previous in vitro studies, and they indicate that telemetry is an accurate method for measuring uterine contraction, and hence parturition, in mice. The use of this technology will lead to important novel insights into changes in intrauterine pressure during the course of pregnancy.

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