| Autor: |
Maier, Lars S., Wahl-Schott, Christian, Horn, Wiebke, Weichert, Stefan, Pagel, Christian, Wagner, Stefan, Dybkova, Nataliya, Müller, Oliver J., Näbauer, Michael, Franz, Wolfgang-M., Pieske, Burkert |
| Předmět: |
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| Zdroj: |
Cardiovascular Research; Sep2005, Vol. 67 Issue 4, p636-646, 11p |
| Abstrakt: |
Abstract: Objective: Heart failure is associated with reduced function of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) but increased function of sarcolemmal Na+ /Ca2+ exchanger (NCX), leading to decreased SR Ca2+ content and loss of frequency-potentiation of contractile force. We reported that SERCA2a-overexpression in transgenic rat hearts (TG) results in improved contractility. However, it was not clear whether TG have improved contractility due to frequency-dependent improved SR Ca2+ handling. Methods: Therefore, we characterized TG (n =35) vs. wild-type (WT) control rats (n =39) under physiological conditions (37 °C, stimulation rate <8 Hz). Twitch force, intracellular Ca2+ transients ([Ca2+]i), and SR Ca2+ content were measured in isolated muscles. The contribution of transsarcolemmal Ca2+ influx (I Ca) through L-type Ca2+ channels (LTCC) and reverse mode NCX (I Na/Ca) to Ca2+ cycling were studied in isolated myocytes. Results: With increasing frequency, force increased in TG muscles by 168±35% (8 Hz; P <0.05) and SR Ca2+ content increased by maximally 118±31% (4 Hz; P <0.05). In WT, there was a flat force-frequency response without changes in SR Ca2+ content. Relaxation parameters of force and [Ca2+]i decay were accelerated at each frequency in TG vs. WT by ∼10%. At prolonged rest intervals (<240 s), force and SR Ca2+ content increased significantly more in TG. Consequently, absolute SR Ca2+ content measured in myocytes was increased ∼2-fold in TG. Transsarcolemmal Ca2+ fluxes estimated by I Ca (at 0 mV −10.2±1.1 vs. −16.9±1.3 pA/pF) and I Na/Ca (0.17±0.02 vs. 0.46±0.05 pA/pF) were decreased in TG vs. WT (P <0.05), whereas NCX and LTCC protein expression was only slightly reduced (P =n.s.). Conclusion: In summary, SERCA2a-overexpression improved contractility in a frequency-dependent way due to increased SR Ca2+ loading whereas transsarcolemmal Ca2+ fluxes were decreased. [Copyright &y& Elsevier] |
| Databáze: |
Complementary Index |
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