Increased SR Ca cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats

Maier, Lars S.; Wahl‐Schott, Christian; Horn, W; Weichert, Stefan; Pagel, C; Wagner, Stefan; Dybkova, Nataliya; Müller, Oliver; Näbauer, Michael; Franz, Wolfgang M.

doi:10.1016/j.cardiores.2005.05.006

Cited by 31 publications

(14 citation statements)

References 46 publications

(49 reference statements)

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“…The modified Ca 2+ handling system in β 3 -KNO mice stands in contrast to the fact that contractility and morphology of the hearts exposed to chronic β 3 -adrenoceptor deficiency did not differ to WT hearts in the parameters measured. Studies performed in rats showing over-expression of SERCA 2a showed improved contractility under baseline conditions and pressure overload [44] due to increased calcium load of the SR [39]. Working heart preparations of SERCA 2a over-expressing rats showed improved systolic and diastolic parameters, whereas β 3 -KNO mice showing increased SERCA 2a expression showed no change in the ultrasonographically measured systolic and diastolic parameters.…”

Section: Discussionmentioning

confidence: 96%

Increased Ca2+ sensitivity and protein expression of SERCA 2a in situations of chronic β3-adrenoceptor deficiency

Ziskoven

Grafweg

Bölck

et al. 2006

Pflugers Arch - Eur J Physiol

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This study investigated the influence of chronic beta(3)-adrenoceptor deficiency on myocardial function. Therefore, we investigated Ca(2+)-regulatory proteins, SERCA 2a activity, and myofibrillar and mitochondrial function in hearts of wild-type (WT, n=7) and beta(3)-adrenoceptor knockout mice (beta(3)-KNO, n=7). Morphometric heart analysis showed no difference between WT and beta(3)-KNO. No alterations were observed for the protein expression of the ryanodine receptor or phospholamban. However, in beta(3)-KNO mice, protein expression of SERCA 2a and phospholamban phosphorylation were significantly increased. These changes were accompanied by an increased SERCA 2a activity in beta(3)-KNO. Alterations in phospholamban phosphorylation were independent of alterations in beta(1)/beta(2)-adrenoceptor distribution and protein expression of G proteins in beta(3)-KNO. Measurement of myofibrillar Ca(2+) sensitivity showed no difference in the Ca(2+)/force relation for WT and beta(3)-KNO. The same seems to hold true for mitochondrial function since the protein expressions of cytochrome c, uncoupling protein 3 and cytochrome c oxidase subunit IV were similar in WT and beta(3)-KNO. The conclusion is that depression of beta(3)-adrenergic stimulation may modulate the protein expression of SERCA 2a and phospholamban phosphorylation, thereby improving sarcoplasmic reticulum Ca(2+) uptake. Thus, beta(3)-adrenergic depression may be a therapeutic aim in situations of impaired SERCA 2a activity, e.g. for the treatment of heart failure.

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Section: Discussionmentioning

confidence: 96%

Increased Ca2+ sensitivity and protein expression of SERCA 2a in situations of chronic β3-adrenoceptor deficiency

Ziskoven

Grafweg

Bölck

et al. 2006

Pflugers Arch - Eur J Physiol

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“…In rats, hemodynamic deterioration and myocarditis have been reported after 3 weeks of immunization with cardiac a-myosin or a-myosin peptides [173,305]. This was associated with increased expression and activity of inducible nitric oxide synthase (iNOS) and an inhibitor of that enzyme effectively attenuated the histopathologic changes, thus pointing to a relevant pathophysiologic role of nitric oxide (NO) [103,104].…”

Section: Myocarditis-induced Hfmentioning

confidence: 99%

Rodent models of heart failure: an updated review

et al. 2012

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Heart failure (HF) is one of the major health and economic burdens worldwide, and its prevalence is continuously increasing. The study of HF requires reliable animal models to study the chronic changes and pharmacologic interventions in myocardial structure and function and to follow its progression toward HF. Indeed, during the past 40 years, basic and translational scientists have used small animal models to understand the pathophysiology of HF and find more efficient ways of preventing and managing patients suffering from congestive HF (CHF). Each species and each animal model has advantages and disadvantages, and the choice of one model over another should take them into account for a good experimental design. The aim of this review is to describe and highlight the advantages and drawbacks of some commonly used HF rodents models, including both non-genetically and genetically engineered models, with a specific subchapter concerning diastolic HF models.

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“…3C). SERCA2a activity controls both the rate of cytosolic Ca 2 + removal and the extent of SR Ca 2 + load (Maier et al, 2005), thereby affecting both LV relaxation and contraction (He et al, 1997). Although we did not directly measure SR Ca 2 + loading, this effect of increased SERCA2a is anticipated, and is reflected in the substantial increases in LV + dP/dt ( Figs.…”

mentioning

confidence: 97%

Intravenous Adeno-Associated Virus Serotype 8 Encoding Urocortin-2 Provides Sustained Augmentation of Left Ventricular Function in Mice

et al. 2013

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Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask whether a single intravenous injection of adeno-associated virus type 8 encoding murine urocortin-2 (AAV8.UCn2) could provide long-term elevation in plasma UCn2 levels and increased left ventricular (LV) function. Normal mice received AAV8.UCn2 (5 · 10 11 genome copies, intravenous). Plasma UCn2 increased 15-fold 6 weeks and > 11-fold 7 months after delivery. AAV8 DNA and UCn2 mRNA expression was persistent in LV and liver up to 7 months after a single intravenous injection of AAV8.UCn2. Physiological studies conducted both in situ and ex vivo showed increases in LV + dP/dt and in LV -dP/dt, findings that endured unchanged for 7 months. SERCA2a mRNA and protein expression was increased in LV samples and Ca 2 + transient studies showed an increased rate of Ca 2 + decline in cardiac myocytes from mice that had received UCn2 gene transfer. We conclude that a single intravenous injection of AAV8.UCn2 increases plasma UCn2 and increases LV systolic and diastolic function for at least 7 months. The simplicity of intravenous injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy in clinical settings. Future studies will determine the usefulness of this approach in the treatment of heart failure.

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Increased SR Ca cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats

Abstract: In summary, SERCA2a-overexpression improved contractility in a frequency-dependent way due to increased SR Ca2+ loading whereas transsarcolemmal Ca2+ fluxes were decreased.

Cited by 31 publications

References 46 publications

Increased Ca2+ sensitivity and protein expression of SERCA 2a in situations of chronic β3-adrenoceptor deficiency

Increased Ca2+ sensitivity and protein expression of SERCA 2a in situations of chronic β3-adrenoceptor deficiency

Rodent models of heart failure: an updated review

Intravenous Adeno-Associated Virus Serotype 8 Encoding Urocortin-2 Provides Sustained Augmentation of Left Ventricular Function in Mice

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