Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Hulot, Jean‐Sébastien; Senyei, Grant; Rj, Hajjar

doi:10.1038/gt.2012.34

Cited by 13 publications

(14 citation statements)

References 51 publications

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“…Excessive PP1 activation is opposed by its endogenous inhibitor, PP1 inhibitor-1, so that normalization of PP1 activity through upregulation of PP1 inhibitor-1 represents a novel molecular therapy directed to improve calcium regulation in heart failure 5 . Importantly, various calcium cycling proteins that modulate SERCA-2a/PLN function are now addressable by gene therapy 5,7,8 . Nevertheless, the upstream molecular signals linked to impaired SERCA-2a/PLN function in heart failure are unknown.…”

mentioning

confidence: 99%

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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mentioning

confidence: 99%

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

Traister

Aafaqi

et al. 2014

Nat Commun

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“…Heart failure is the leading cause of mortality and morbidity in Western countries and a common endpoint of cardiac disorders, including atherosclerosis, ischemic cardiomyopathies, familiar cardiomyopathies, valvular-induced myocardial pathologies and arterial hypertension [1], [2]. A common feature of heart failure is an altered Ca 2+ homeostasis, which is a consequence of dysregulation of Ca 2+ cycling proteins.…”

Section: Introductionmentioning

confidence: 99%

A Novel Artificial MicroRNA Expressing AAV Vector for Phospholamban Silencing in Cardiomyocytes Improves Ca2+ Uptake into the Sarcoplasmic Reticulum

et al. 2014

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In failing rat hearts, post-transcriptonal inhibition of phospholamban (PLB) expression by AAV9 vector-mediated cardiac delivery of short hairpin RNAs directed against PLB (shPLBr) improves both impaired SERCA2a controlled Ca2+ cycling and contractile dysfunction. Cardiac delivery of shPLB, however, was reported to cause cardiac toxicity in canines. Thus we developed a new AAV vector, scAAV6-amiR155-PLBr, expressing a novel engineered artificial microRNA (amiR155-PLBr) directed against PLB under control of a heart-specific hybrid promoter. Its PLB silencing efficiency and safety were compared with those of an AAV vector expressing shPLBr (scAAV6-shPLBr) from an ubiquitously active U6 promoter. Investigations were carried out in cultured neonatal rat cardiomyocytes (CM) over a period of 14 days. Compared to shPLBr, amiR155-PLBr was expressed at a significantly lower level, resulting in delayed and less pronounced PLB silencing. Despite decreased knockdown efficiency of scAAV6-amiR155-PLBr, a similar increase of the SERCA2a-catalyzed Ca2+ uptake into sarcoplasmic reticulum (SR) vesicles was observed for both the shPLBr and amiR155-PLBr vectors. Proteomic analysis confirmed PLB silencing of both therapeutic vectors and revealed that shPLBr, but not the amiR155-PLBr vector, increased the proinflammatory proteins STAT3, STAT1 and activated STAT1 phosphorylation at the key amino acid residue Tyr701. Quantitative RT-PCR analysis detected alterations in the expression of several cardiac microRNAs after treatment of CM with scAAV6-shPLBr and scAAV6-amiR155-PLBr, as well as after treatment with its related amiR155- and shRNAs-expressing control AAV vectors. The results demonstrate that scAAV6-amiR155-PLBr is capable of enhancing the Ca2+ transport function of the cardiac SR PLB/SERCA2a system as efficiently as scAAV6-shPLBr while offering a superior safety profile.

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“…One of the hallmarks of HF and a consequence of dysregulated βAR signaling is abnormal calcium (Ca 2+ ) handling [18,19]. Its major characteristic in the failing cardiac myocyte is decreased expression and activity of the myocardial sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA2a) [20].…”

Section: Ca Cycling Proteinsmentioning

confidence: 99%

Cardiovascular gene therapy for myocardial infarction

Scimia¹,

Gumpert²,

Koch³

2013

Expert Opinion on Biological Therapy

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Introduction Cardiovascular gene therapy is the third most popular application for gene therapy, representing 8.4% of all gene therapy trials as reported in 2012 estimates. Gene therapy in cardiovascular disease is aiming to treat heart failure from ischemic and non-ischemic causes, peripheral artery disease, venous ulcer, pulmonary hypertension, atherosclerosis and monogenic diseases, such as Fabry disease. Areas covered In this review, we will focus on elucidating current molecular targets for the treatment of ventricular dysfunction following myocardial infarction (MI). In particular, we will focus on the treatment of i) the clinical consequences of it, such as heart failure and residual myocardial ischemia and ii) etiological causes of MI (coronary vessels atherosclerosis, bypass venous graft disease, in-stent restenosis). Expert opinion We summarise the scheme of the review and the molecular targets either already at the gene therapy clinical trial phase or in the pipeline. These targets will be discussed below. Following this, we will focus on what we believe are the 4 prerequisites of success of any gene target therapy: safety, expression, specificity and efficacy (SESE).

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Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Cited by 13 publications

References 51 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

A Novel Artificial MicroRNA Expressing AAV Vector for Phospholamban Silencing in Cardiomyocytes Improves Ca2+ Uptake into the Sarcoplasmic Reticulum

Cardiovascular gene therapy for myocardial infarction

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