Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis

Rubio, Marta; Bódi, Ilona; Fuller-Bicer, Geraldine A.; Hahn, Harvey S.; Periasamy, Muthu; Schwartz, Arnold

doi:10.1177/107424840501000404

Cited by 7 publications

(4 citation statements)

References 40 publications

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“…When these mice are interbred with mice overexpressing a skeletal muscle form of the sarcoplasmicendoplasmic reticulum Ca 2+ ATPase (SERCA1a) they develop more marked hypertrophy, increased CaMKII expression, action potential prolongation, afterdepolarizations and arrhythmias [50]. On the other hand, these investigators found that a known CaMKII phosphorylation site on the SERCA regulatory protein phospholamban (threonine 17) was hypo-phosphorylated, suggesting that other uncharacterized compensatory mechanisms are active in this model.…”

Section: Proarrhythmic Electrical Remodelingmentioning

confidence: 99%

Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus

Anderson

2007

Cardiovasc Res

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The multifunctional Ca 2+ calmodulin-dependent protein kinase II (CaMKII) has emerged as a pro-arrhythmic signaling molecule. CaMKII can participate in arrhythmia signaling by effects on ion channel proteins, intracellular Ca 2+ uptake and release, regulation of cell death, and by activation of hypertrophic signaling pathways. The pleuripotent nature of CaMKII is reminiscent of another serine-threonine kinase, protein kinase A (PKA), which shares many of the same protein targets and is the downstream kinase most associated with β-adrenergic receptor stimulation. The ability of CaMKII to localize and coordinate activity of multiple protein targets linked to Ca 2+ signaling set CaMKII apart from other "traditional" arrhythmia drug targets, such as ion channel proteins. This review will discuss some of the biology of CaMKII and focus on work that has been done on molecular, cellular, and whole animal models that together build a case for CaMKII as a pro-arrhythmic signal and as a potential therapeutic target for arrhythmias and structural heart disease.

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Section: Proarrhythmic Electrical Remodelingmentioning

confidence: 99%

Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus

Anderson

2007

Cardiovasc Res

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“…MA1-980), and monoclonal anti-calsequestrin antibody (1:2,500, PA1-913). Calsequestrin was used as an internal protein content reference (30,47). Membranes were then washed and incubated with secondary antibody for 1 h at room temperature [1:100,000 for c-myc (i.e., SERCA1) and 1:50,000 for SERCA2 and calsequestrin] (goat antimouse horseradish peroxidase-conjugated antibody, Pierce).…”

Section: Methodsmentioning

confidence: 99%

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

O’Donnell

Fields²,

Xu³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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O'Donnell JM, Fields A, Xu X, Chowdhury SA, Geenen DL, Bi J. Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo. Am J Physiol Heart Circ Physiol 295: H2483-H2494, 2008. First published October 24, 2008 doi:10.1152/ajpheart.01023.2008.-Adenoviral gene transfer of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2a to the hypertrophic heart in vivo has been consistently reported to lead to enhanced myocardial contractility. It is unknown if the faster skeletal muscle isoform, SERCA1, expressed in the whole heart in early failure, leads to similar improvements and whether metabolic requirements are maintained during an adrenergic challenge. In this study, Ad.cmv.SERCA1 was delivered in vivo to aortic banded and shamoperated Sprague-Dawley rat hearts. The total SERCA content increased 34%. At 48 -72 h posttransfer, echocardiograms were acquired, hearts were excised and retrograded perfused, and hemodynamics were measured parallel to NMR measures of the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) and energy substrate selection at basal and high workloads (isoproterenol). In the Langendorff mode, the rate-pressure product was enhanced 27% with SERCA1 in hypertrophic hearts and 10% in shams. The adrenergic response to isoproterenol was significantly potentiated in both groups with SERCA1.31 P NMR analysis of PCr/ATP revealed that the ratio remained low in the hypertrophic group with SERCA1 overexpression and was not further compromised with adrenergic challenge.13 C NMR analysis revealed fat and carbohydrate oxidation were unaffected at basal with SERCA1 expression; however, there was a shift from fats to carbohydrates at higher workloads with SERCA1 in both groups. Transport of NADH-reducing equivalents into the mitochondria via the ␣-ketoglutamate-malate transporter was not affected by either SERCA1 overexpression or adrenergic challenge in both groups. Echocardiograms revealed an important distinction between in vivo versus ex vivo data. In contrast to previous SERCA2a studies, the echocardiogram data revealed that SERCA1 expression compromised function (fractional shortening) in the hypertrophic group. Shams were unaffected. While our ex vivo findings support much of the earlier cardiomyocyte and transgenic data, the in vivo data challenge previous reports of improved cardiac function in heart failure models after SERCA intervention. sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; glucose oxidation; fatty acid oxidation; phosphocreatine-to-ATP ratio; myocardial energy potential THE CHANGES in intracellular Ca 2ϩ handling reported for the failing myocardium have been linked to sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA). Calcium uptake into the sarcoplasmic reticulum (SR) by SERCA determines the rate of calcium removal for relaxation, the SR calcium content, and calcium released for contractions (33,45). In the failing heart, it has been proposed that SERCA contributes to reduced contractil...

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“…SERCA plays a major role in the regulation of intracellular Ca 2+ and directly affects myocardial function. Increase or decrease in SERCA activity may lead to heart failure and arrhythmia ( 17 ). Moreover, the reduced activity or expression of SERCA2a may lead to myocardial cell dysfunction ( 3 ).…”

Section: Discussionmentioning

confidence: 99%

Testosterone suppresses ventricular remodeling and improves left ventricular function in rats following myocardial infarction

Wang

Zhang

et al. 2015

Experimental and Therapeutic Medicine

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Men with congestive heart failure (CHF) have relatively low testosterone levels. Several studies demonstrated that testosterone treatment increases cardiac output and reduces peripheral vascular resistance. However, the effects of testosterone on heart function, cardiomyocyte apoptosis and ventricular remodeling have not been fully elucidated. This study was conducted to investigate the effects of testosterone on heart function, cardiomyocyte apoptosis and ventricular remodeling in male rats post-myocardial infarction. A total of 86 male rats were randomly assigned to undergo ligation of the coronary artery (n=70) or pseudosurgery (n=16). After 6 weeks, a left ventricular ejection fraction (LVEF) of ≤45% was defined as a successful model of CHF. The model rats were randomly assigned to 3 groups, namely low-dose testosterone (TU), high-dose TU and placebo (PL) groups. After treatment for 12 weeks, the expression of several mRNA transcripts in myocardial tissue was measured by quantitative polymerase chain reaction. Immunofluorescence was used to measure myocardial caspase-3 expression. Compared to the PL group, LVEF was significantly improved in the TU treatment groups. Moreover, the mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-2 and sarcoendoplasmic reticulum Ca2+-ATPase 2a was significantly reduced, while the mRNA expression of glycogen synthase kinase 3β and tissue inhibitor of metalloproteinase-2 was markedly increased in the TU groups. TU treatment also significantly reduced caspase-3 expression. Therefore, different doses of TU suppressed ventricular remodeling and improved left ventricular function, reduced apoptosis and prevented mortality in a CHF rat model.

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Sarcoplasmic Reticulum Adenosine Triphosphatase Overexpression in the L-type Ca2+ Channel Mouse Results in Cardiomyopathy and Ca2+-Induced Arrhythmogenesis

Abstract: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca(2+) cycling in arrhythmogenesis.

Cited by 7 publications

References 40 publications

Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus

Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

Testosterone suppresses ventricular remodeling and improves left ventricular function in rats following myocardial infarction

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