SERCA2a Gene Transfer Decreases Sarcoplasmic Reticulum Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure

Lyon, Alexander R.; Bannister, Mark L.; Collins, Tom; Pearce, Emma; Sepehripour, Amir H.; Dubb, Sukhpreet Singh; García, Edwin; O’Gara, Peter; Liang, Lifan; Kohlbrenner, Erik; Hajjar, Roger J.; Peters, Nicholas S.; Poole‐Wilson, Philip A.; MacLeod, Ken; Harding, Siân E.

doi:10.1161/circep.110.961615

Cited by 157 publications

(159 citation statements)

References 42 publications

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“…4c). This result is in agreement with the reduction in provokable ventricular arrhythmias observed following SERCA-2a gene therapy in a swine infarction model attributable to stabilization of SR calcium loading 53 .…”

Section: Resultssupporting

confidence: 89%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK R211A ) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

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Section: Resultssupporting

confidence: 89%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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“…In these earlier studies, SERCA2a gene therapy was effective in suppressing triggered activity by reducing SR calcium leak and spontaneous calcium waves 7. Unlike in rodents, however, complex arrhythmias in humans and large animals require an appropriate electrophysiological substrate that converts calcium‐mediated triggers into sustained VT/VF.…”

Section: Discussionmentioning

confidence: 99%

“…A key question is whether accelerating intracellular Ca 2+ cycling using SERCA2a gene therapy suppresses or promotes post‐MI arrhythmias. In rodents, SERCA2a overexpression ameliorated triggered activity by decreasing ryanodine receptor–mediated Ca 2+ leak 7. However, unlike in rodents, post‐MI arrhythmias in large animals and humans require an adverse electrophysiological substrate that is capable of converting Ca 2+ ‐mediated triggers to sustained VT/VF.…”

Section: Introductionmentioning

confidence: 99%

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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Background SERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.Conclusions SERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.

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“…Subsequently, a number of studies have shown beneficial effects on cardiac structure, contractility, Ca cycling (including reduced Ca leak), and myocardial energetics after SERCA gene delivery, either via direct intramyocardial injection or via coronary perfusion, in diverse models of heart failure. [26][27][28][29] There are several potential problems that may arise as a consequence of attempts to increase SERCA activity in heart failure. These include an increase in energy/oxygen demand because of the requirement for ATP hydrolysis to drive the increased Ca transport by SERCA.…”

Section: Targeting Serca Directly-from Bench To Clinical Trialmentioning

confidence: 99%

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Eisner

Caldwell

Trafford

2013

Circulation Research

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T his article reflects on the impact of a classic paper identifying the effects of loss of sarcoplasmic reticulum Ca-ATPase activity in heart failure. The Classic ArticleUnderstanding the effects of heart failure on contraction and Ca signaling in the heart has long been a priority. By the late 1980s, many studies on animal models had shown that heart failure resulted in a slowing of the decay of the systolic Ca transient 1 because of a decrease in the expression of the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA).2 Work using human tissue found similar changes.3,4 In 1994, Hasenfuss et al 5 published a now classic article in Circulation Research entitled "Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and non-failing human myocardium." Previous work had shown that SERCA expression and activity were decreased in heart failure. Other work had shown that the increase of force seen on increasing the frequency of stimulation (the positive forcefrequency curve) disappeared in heart failure. Hasenfuss et al 5 showed that the degree of change in the force-frequency relationship correlated with the loss of SERCA. Hearts with low levels of SERCA developed maximum force at lower frequencies than those with higher levels. In addition, and suggested as causative of the reduced force-frequency responses, the failing hearts had reduced SERCA-mediated Ca uptake.The work in this article has influenced 2 areas of research: changes of SR function in heart failure and restoration of SERCA as a therapeutic strategy. We consider these in turn. SR Function in Heart FailureTwenty years later, the role of changes of SERCA expression in heart failure is well-established. The majority of studies of heart failure in either humans or experimental animals show that SERCA activity is decreased in heart failure. This decrease of SERCA has 2 immediate effects on Ca signaling. First, it slows the rate of decay of the systolic Ca transient, thereby impairing relaxation. Second, as a consequence of decreasing SR Ca content, it will decrease the amplitude of the systolic Ca transient and thus contraction. However, subsequent work has shown that changes of SERCA are part of a group of changes of Ca signaling that occur in heart failure. As highlighted in Figure, 2 other factors will also decrease the SR Ca content. First, there is an increase of NCX expression or activity. [6][7][8] This adaptation has the benefit of making up for the reduced SERCA, thereby preserving relaxation. In a subsequent article, Hasenfuss et al 9 showed that patients with increased NCX had better diastolic function than did those with lower NCX. However, although increased NCX improves diastolic function, it will decrease SR Ca content and thereby depress systolic function further. Second, many studies have now shown that the open probability of the RyR is increased in heart failure. [10][11][12] This may occur as a result of phosphorylation, 10 hyponitrosylation, 13 or oxidation. 14 This increased opening will lead to a...

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SERCA2a Gene Transfer Decreases Sarcoplasmic Reticulum Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure

Cited by 157 publications

References 42 publications

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

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