| Autor: |
Uwe Rehfeld, Martin Paul, Roland Vetter, Wolfgang Weiß, Wolfgang H. Dillmann, Christoph Reissfelder, Joachim Günther, Kay-Dietrich Wagner |
| Rok vydání: |
2003 |
| Předmět: |
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| Zdroj: |
Cardiac Remodeling and Failure ISBN: 9781461348641 |
| DOI: |
10.1007/978-1-4419-9262-8_28 |
| Popis: |
Cardiac relaxation partially depends on the expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on cardiac SR Ca2+ handling under normal and pathological conditions we generated a new transgenic rats model expressing a human cytomegalovirus enhancer/chicken β-actin promotor-controlled rat SERCA2a transgene. Characterization of a heterozygous transgenic rat line (L1167) showed that the steady-state SERCA2 mRNA and protein levels increased by +69% and +25%, respectively, relative to wild-type rats. The levels of mRNA encoded by some of the other genes involved in cardiac Ca2+ control, such as phospholamban and Na+/Ca2+ exchanger, remained unchanged. Functional analysis of SR Ca2+ handling in isolated membranes in the presence of the synthetic protein kinase A inhibitor peptide [PKI (6–22)amide] indicated that the rate of oxalate-supported Ca2+ uptake was increased in average by 49% at free Ca2+ concentrations ranging from 0.5 to 3.7 μM if compared to wild-type controls. The sensitivity of uptake to the specific SR Ca2+-ATPase inhibitor thapsigargin was similar in transgenic and wild-type animals (IC50:3.4 ± 0.7 vs. 3.8 ± 0.4 nM, respectively). Cardiac expression of the SERCA2a transgene also occurred in streptozotocin-induced diabetes mellitus and propylthiouracil-induced hypothyroidism and this rescued, at least partially, the compromised cardiac SR Ca2+ transport in these diseased conditions. At 3.7 μM free Ca2+, homogenate SR Ca2+ uptake of hypothyroid and diabetic transgenic animals was 42% and 33% higher than in respective diseased hearts of wild-type rats (p < 0.05, respectively). Our results suggest that transgenic rats overexpressing SERCA2a can serve as a valid model for further evaluation concerning the possible therapeutic impact of specifically targeting gene expression of the SR Ca2+-ATPase under pathological conditions with compro- mised cardiac SR Ca2+ transport. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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