Targeting S100A1 in heart failure

Ritterhoff, Julia; Most, Patrick

doi:10.1038/gt.2012.8

Cited by 43 publications

(48 citation statements)

References 66 publications

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“…On the other hand, only a subfraction of S100A1 was associated with the RyR2 (Figure 1d), in line with S100A1's different subcellular localizations and interacting partners (Sarcoplasmic reticulum, mitochondria, myofilmants; reviewed in ref. 16 ). To investigate the interaction of S100A1 and RyR2 in failing hearts, myocardial infarction in C57BL/6 mice was performed that resulted in impaired cardiac performance after 2 weeks as demonstrated by left ventricular catheterization (Supplementary Figure S1a).…”

Section: Results S100a1 Interaction With Ryr2 Is Decreased In Postiscmentioning

confidence: 99%

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S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction

et al. 2015

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Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca(2+) leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca(2+)- and β-adrenergic receptor-triggered proarrhythmogenic SR Ca(2+) leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca(2+) leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca(2+) leak in HF, combining antiarrhythmic potency with chronic inotropic actions.

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Section: Results S100a1 Interaction With Ryr2 Is Decreased In Postiscmentioning

confidence: 99%

“…15 One such candidate might be S100A1, an EF-hand Ca 2+ sensor protein that is highly expressed in cardiomyocytes (reviewed in refs. 16,17 ). Diminished S100A1 protein expression, which is characteristic of advanced human HF, accelerates transition to contractile failure and exacerbates mortality in experimental HF models.…”

Section: Introductionmentioning

confidence: 99%

S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction

et al. 2015

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“…The Ca 2+ binding protein S100A1 has been shown to interact with various Ca 2+ handling proteins (such as RyR and SERCA) (Figure 1) and affect their activities [32]. S100A1 expression is decreased in heart failure.…”

Section: Endogenous Calcium Handling Proteinsmentioning

confidence: 99%

Calcium mishandling in diastolic dysfunction: Mechanisms and potential therapies

Michelle

Martindale

Heinis

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Diastolic dysfunction is characterized by slow or incomplete relaxation of the ventricles during diastole, and is an important contributor to heart failure pathophysiology. Clinical symptoms include fatigue, shortness of breath, and pulmonary and peripheral edema, all contributing to decreased quality of life and poor prognosis. There are currently no therapies available that directly target the heart pump defects in diastolic function. Calcium mishandling is a hallmark of heart disease and has been the subject of a large body of research. Efforts are ongoing in a number of gene therapy approaches to normalize the function of calcium handling proteins such as sarcoplasmic reticulum calcium ATPase. An alternative approach to address calcium mishandling in diastolic dysfunction is to introduce calcium buffers to facilitate relaxation of the heart. Parvalbumin is a calcium binding protein found in fast-twitch skeletal muscle and not normally expressed in the heart. Gene transfer of parvalbumin into normal and diseased cardiac myocytes increases relaxation rate but also markedly decreases contraction amplitude. Although parvalbumin binds calcium in a delayed manner, it is not delayed enough to preserve full contractility. Factors contributing to the temporal nature of calcium buffering by parvalbumin are discussed in relation to remediation of diastolic dysfunction.

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“…Other molecular targets for gene therapy that are associated with abnormal Ca 2+ cycling include the S100A1 protein, which is downregulated in HF, 102 and phospholamban. The β-adrenergic receptor kinase carboxy terminal peptide and adenylylcyclase 6 are also candidates for HF gene therapy with the hope that they will improve β-adrenergic responsiveness.…”

Section: Gene Therapy For Hfmentioning

confidence: 99%

Research Advances in Heart Failure

Braunwald

2013

Circulation Research

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W ithout question, the past half century has witnessed spectacular advances in cardiovascular medicine and surgery. In the United States, a full two thirds of the 6-year prolongation of life that has occurred has been a direct consequence of these advances 1 that did not spring forth simply from the heads of brilliant, insightful clinicians. Instead, most advances were based on preclinical research that were then translated into improvements in clinical care. 2 For instance, the microbiologists who connected streptococcal infection to acute rheumatic fever and, subsequently, the discovery of penicillin by a microbiologist, an experimental pathologist, and a biochemist led to the virtual elimination of acute rheumatic fever, which in turn was responsible for the marked reduction of chronic rheumatic valvular heart disease in large portions of the world. Almost all residual cases of the latter can now be corrected by open heart surgery or catheter-based techniques, which were made possible by the efforts of bioengineers, pharmacologists, and physiologists collaborating with surgeons and cardiologists. The striking reduction in mortality of acute myocardial infarction that has occurred since 1960 3 would not have been possible had physicists not previously developed the cathode ray oscilloscope, which enabled the continuous monitoring of the ECG, and if engineers had not developed the capacitors that store the electric charge required for ventricular defibrillation. Without pharmacologists and cell biologists, statins, which are enormously useful in preventing the development and progression of atherosclerosis, would not have been developed. These are just a few examples of the seminal scientific efforts that have provided the underpinnings of modern cardiology.However, despite the spectacular advances of the past half century, cardiovascular disease is still the most common cause of death and disability in industrialized nations, 4 and its prevalence is rising rapidly in developing nations. Almost one half of all cardiac deaths and disabilities are related to failure to apply well-established, evidence-based, guideline-approved therapies and preventive measures. These failures stem largely from inadequate access to care, poverty, and the disorganization of the medical care system in many countries, and they require political, economic, and societal changes. The remaining cardiovascular events, still a major problem in public health, result in large measure from the deficiencies in our understanding of cardiovascular pathobiology. Heart Failure Compendium© 2013 American Heart Association, Inc. One major disorder, heart failure (HF), remains a stubborn problem and is now considered to be the greatest challenge in cardiovascular medicine and surgery.5 From a clinical perspective, HF has been defined as "a complex syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance a...

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Targeting S100A1 in heart failure

Cited by 43 publications

References 66 publications

S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction

S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction

Calcium mishandling in diastolic dysfunction: Mechanisms and potential therapies

Research Advances in Heart Failure

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