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From hypertrophy to heart failure-the role of spontaneous SR Ca2+ leak

Abstract

Heart failure (HF) is a leading cause of death in the developed countries. Despite considerable progress in the past decade in our understanding of cellular and molecular mechanisms involved in the progression of HF, therapeutic agents that specifically target the underlying cellular defects remain rare and ineffective. In HF, intracellular Ca2+ homeostasis is altered and increased cytosolic Ca2+ has been proposed as a potential activator of hypertrophic signalling cascades, ultimately culminating in overt HF phenotype. Recent studies pointed out that increased spontaneous Ca2+ release (Ca2+ leak) from the sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR2) due to defective regulation of the RyR2 occurs during HF and causes contractile dysfunction and development of arrhythmias. However, it remains controversial whether increased SR Ca2+ leak is an epiphenomenon accompanying HF only or a pathophysiologically relevant process contributing to accelerated decompensation from hypertrophy to HF.
In the proposed project, we will pursue the hypothesis, that an increased spontaneous SR Ca2+ leak per se is causally involved in accelerated decompensation from cardiac hypertrophy to HF. We will take advantage of the minimally invasive transverse aortic constriction (TAC) as a pressure overload model for HF, and apply it to a mouse model with an inherited SR Ca2+ leak (knock-in RyR2R4496C+/- human mutation). Our preliminary results show strikingly increased hypertrophy and accelerated transition from hypertrophy to HF in RyR2R4496C+/- hearts after TAC, confirming our initial hypothesis. In the current project, we aim to identify the mechanism(s) of the transition from hypertrophy to overt HF. We will investigate, whether congenital SR Ca2+ leak in RyR2R4496C+/- cardiomyocytes is increased after TAC and, subsequently, leads to alterations in expression and/or phosphorylation pattern of Ca2+ regulatory proteins and transcription factors involved in Ca2+-dependent hypertrophic signalling pathways. Using in vivo ECG recordings, we will further determine the cause for premature cardiac death in RyR2R4496C+/--TAC mice. Additionally, rescue experiments will reveal, whether a putative RyR2 stabilizer (JTV-519) effectively decelerates the HF progression.
We anticipate that these results will help to define a new role for SR Ca2+ release in the transition from cardiac hypertrophy to HF. Since abnormal RyR2 Ca2+ release is regarded as the underlying mechanism for contractile dysfunction and arrhythmias, this project may contribute to the identification of novel molecular therapeutic targets in HF and thus, possibly improve clinical outcome in HF patients in the future.

Keywords

Ca2+ Leck

Drucklast

Herzinsuffizienz

Remodelling

Ryanodin-Rezeptor Typ 2

Project Leader:

Sedej Simon

Duration:

01.01.2011-31.12.2013

Type of Research

basic research

Staff

Sedej, Simon, Project Leader

MUG Research Units

Division of Cardiology

Funded by

Medizinische Universität Graz, Stiftingtalstraße 6, 8010 Graz, Austria

Project results published

> Cardiomyocyte loss is not required for the progres... J Anat. 2016; 229(1):75-81

> Calcium in the heart- between life and death... Research is the backbone of medicine; RIBOM- 1st Student Research Conference. 2016; 1(1):19-19.-1st International Medical Congress RIBOM; APR 8-9, 2016; Maribor, Slovenia. (ISBN: 978-961-6739-38-9 )

> Pharmacological activation of mitochondrial Ca2+ u... N-S ARCH PHARMACOL. 2015; 388: S34-S34.-81st Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und-Toxikologie-e-V; MAR 10-12, 2015; Kiel, GERMANY.

> Subclinical abnormalities in sarcoplasmic reticulu... J Am Coll Cardiol. 2014; 63(15):1569-1579

> K201 reduces pressure overload-induced myocardial ... Cardiovascular Research. 2014; 103(1):-Frontiers in Cardiovascular Biology; JUL 4-6, 2014; Barcelona, Spain.

> Gain-of-function defect in the ryanodine receptor ... Wiener klinische Wochenschrift. 2013; Supplement 01/13(125):14-14.-Österreichische Kardiologische Gesellschaft Jahrestagung 2013; JUN 5-8, 2013; Salzburg, Austria. (ISBN: 0043-5325 )

> Gain-of-function defect in the ryanodine receptor ... DSI European User Group Meeting; MAR 21-22, 2013; Berlin, Deutschland. 2013.

> RyR2-mediated Ca2+ leak in myocardial remodeling: ... 78. Jahrestagung 2012 der Deutschen Gesellschaft für Kardiologie; APR 11-14, 2012; Mannheim. 2012.

> Ryanodine receptor mutation (R4496C+/-) facilitate... Eur J Heart Fail Suppl (2012) . 2012; 11(suppl1):S17-S17.-ESC Heart Failure 2012; May 19-22, 2012; Belgrade, SERBIA .

> Gain-of-function defect in the RyR2R4496C+/- promo... Clin Res Cardiol 2011; 100(1):-77. Jahrestagung der Deutschen Gesellschaft für Kardiologie (DGK); APR 27-30, 2011; Mannheim, DEUTSCHLAND. (ISBN: 1861-0684 )

> Increased Heart Failure Development After Pressure... Biophys J. 2011; 100(3):291a--Annual Meeting of the Biophysical Society; MAR 5-9,2011; Baltimore,USA.

> Accerelated transition of pressure overload-induce... European Journal of Heart Failure Supplements (2010) 9, S114 doi:10.1093/eurjhf/hsq011 2010; 9: S114-S115.-ESC Heart Failure 2010; MAI 29- JUNI 1; Berlin, GERMANY.