Cardiac ryanodine receptors (RyR2) play a central role in the process of excitation-contraction coupling in the heart. Alterations in RyR2 regulation are evident in a variety of cardiovascular diseases. Changes in the phosphorylation status of RyR2 have been described in patients with atrial fibrillation (AF), but the underlying abnormal mechanisms remain poorly understood. Considerable evidence suggests that RyR2 channels comprise a macromolecular complex with regulatory subunits including protein kinases and phosphatases. Studies in human atrial tissue and myocytes as well as experiments in knock-in mouse models have revealed that increased RyR2 phosphorylation predisposes to atrial ectopy and progression of AF. Our preliminary data suggest that alterations in the RyR2-bound protein phosphatases (PPs) might underlie elevated RyR2 phosphorylation in AF, although very little is currently known about this. The long-term goal of this project is to define the cellular/molecular mechanisms by which PPs regulate RyR2 activity in both normal hearts and in humans/mice with AF. The present proposal will test the general hypothesis that variation in levels of PP regulatory subunits associated with RyR2 contributes to enhanced sarcoplasmic reticulum (SR) Ca leak and vulnerability to AF.
Specific aim (1) will use biochemical and genetic approaches to dissect the role of PPs in the regulation of RyR2 phosphorylation.
Specific aim (2) will examine the effects of PP regulation of RyR2 on SR Ca handling in atrial cells using genetic mouse models.
Specific aim (3) will determine the role of PP regulation of RyR2 in atrial fibrillation in vivo in mouse models. Significance: Abnormal RyR2-mediated SR Ca leak has been associated with increased propensity to AF, the most prevalent type of cardiac arrhythmia. The mechanisms will be studied at the molecular, cellular and in vivo level, using recombinant proteins, genetic mouse models and human atrial biopsies. It is anticipated that these multidisciplinary studies will provide fundamental and new insights into the molecular mechanisms by which the RyR2 calcium release channel becomes dysregulated in AF. These insights may guide future developments of anti-arrhythmic drugs for the treatment of AF.
The proposed work will study how the intracellular calcium release channel/ ryanodine receptor is regulated by protein phosphatases in the heart. Moreover, we will study how defective phosphatase regulation of these channels contributes to atrial fibrillation, the most common sustained cardiac arrhythmia in the US.
|Lezcano, N; Mariángelo, J I E; Vittone, L et al. (2018) Early effects of Epac depend on the fine-tuning of the sarcoplasmic reticulum Ca2+ handling in cardiomyocytes. J Mol Cell Cardiol 114:1-9|
|Yao, Chunxia; Veleva, Tina; Scott Jr, Larry et al. (2018) Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation. Circulation 138:2227-2242|
|Ni, Li; Scott Jr, Larry; Campbell, Hannah M et al. (2018) Atrial-Specific Gene Delivery Using an Adeno-Associated Viral Vector. Circ Res :|
|Auguste, Gaelle; Gurha, Priyatansh; Lombardi, Raffaella et al. (2018) Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies. Circ Res 122:678-692|
|Dobrev, Dobromir; Wehrens, Xander H T (2018) Mouse Models of Cardiac Arrhythmias. Circ Res 123:332-334|
|Wang, Qiongling; Quick, Ann P; Cao, Shuyi et al. (2018) Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol 11:e005682|
|Wehrens, Xander H T (2018) Unraveling the Mechanisms by Which Calpain Inhibition Prevents Heart Failure Development. JACC Basic Transl Sci 3:518-520|
|Chiang, David Y; Alsina, Katherina M; Corradini, Eleonora et al. (2018) Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression. Circulation 138:1569-1581|
|Klipp, Robert C; Li, Na; Wang, Qiongling et al. (2018) EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2. Heart Rhythm 15:578-586|
|Pan, Xiaolu; Philippen, Leonne; Lahiri, Satadru K et al. (2018) In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia. Circ Res 123:953-963|
Showing the most recent 10 out of 130 publications