The overall goal of this project is to identify cellular and molecular triggers that promote heart failure (HF) and to determine novel molecular-targeted therapeutic strategies to treat them. The central hypothesis is that HF can be caused by disruption of molecular signaling complexes and processes that, in normal hearts, underlie balanced regulation of cellular activity and that altered cellular calcium (Ca2+) homeostasis plays a critical role in HF progression. This project focuses on elucidating defects in the regulation of type 2 ryanodine receptor (RyR2)/Ca2+ release channel, which is required for cardiac excitation-contraction (EC) coupling. In the previous period of this project the PI showed that a diastolic SR Ca2+ """"""""leak"""""""" via defective RyR2 can contribute to SR Ca depletion and impaired contractility in HF. The PI identified a defect in RyR2 in patients with HF: """"""""leaky"""""""" PKA hyperphosphorylated and oxidized RyR2 channels that exhibit decreased binding affinity for the stabilizing subunit calstabin2 (FKBP12.6). This observation has directly lead to the development of a novel potential therapy for HF, RyCal (S36, which is a JTV-519 derivative without HERG and L-type channel blocking activities), representing a new class of intracellular calcium channel stabilizers that improve cardiac function in murine and canine HF models and are now in Phase II trials in patients with class II and III HF. The PI showed that the phosphodiesterase PDE4D3 is a component of the RyR2 complex and is """"""""protective"""""""" against HF because mice that are deficient in PDE4D3 are predisposed to HF following MI. Moreover, oxidation of RyR2 depletes the channel of PDE4D3 and calstabin2 rendering the channel leaky and promoting HF progression. The PI proposes to test the hypothesis of a """"""""vicious cycle"""""""" between RyR2 and mitochondria due to Ca2+ leak via RyR2 that poisons mitochondria resutling in increased ROS prodcution which further oxidizes RyR2 and exacerbates the leak.
Two aims are proposed: 1) determine whether RyR2 mediated intracellular Ca2+ leak causes mitcondrial dysfunction in HF using RyR2-S2808D mice with constitutively """"""""leaky"""""""" RyR2 channels;and 2) determine whether mitochondrial ROS are responsible for depletion of the RyR2 complex of calstabin2 and PDE4D3 and whether targeting of catalase to mitochondria reduces RyR2-mediated Ca2+ leak and protects against HF progression in the post-MI model. The proposed studies are significant because they will provide novel insights concerning the mechanisms of HF progression.
Under conditions of stress including heart failure and muscular dystrophy ryanodine receptor/calcium release channels become """"""""leaky"""""""". This intracellular calcium leak can drive heart failure progressive, trigger fatal cardiac arrhythmias, and promote muscle damage and decrease exercise capacity in muscular dystrophy animal models. A novel class of drugs called """"""""rycals"""""""" target the RyR mediated intracellular calcium leak and slow heart failure progression, prevent cardiac arrhythmias, and improve exercise capacity in animal models. A rycal is now in Phase II clinical trials for heart failure and cardiac arrhythmias. Thus, gaining new understandings of how the RyR/calcium release channels are regulated has important implications for developing novel therapies for heart and muscle diseases.
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|des Georges, Amédée; Clarke, Oliver B; Zalk, Ran et al. (2016) Structural Basis for Gating and Activation of RyR1. Cell 167:145-157.e17|
|Xie, Wenjun; Santulli, Gaetano; Reiken, Steven R et al. (2015) Mitochondrial oxidative stress promotes atrial fibrillation. Sci Rep 5:11427|
|Zalk, Ran; Clarke, Oliver B; des Georges, Amédée et al. (2015) Structure of a mammalian ryanodine receptor. Nature 517:44-9|
|Cheung, Jim W; Meli, Albano C; Xie, Wenjun et al. (2015) Short-coupled polymorphic ventricular tachycardia at rest linked to a novel ryanodine receptor (RyR2) mutation: leaky RyR2 channels under non-stress conditions. Int J Cardiol 180:228-36|
|Santulli, Gaetano; Marks, Andrew R (2015) Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging. Curr Mol Pharmacol 8:206-22|
|Santulli, Gaetano; Xie, Wenjun; Reiken, Steven R et al. (2015) Mitochondrial calcium overload is a key determinant in heart failure. Proc Natl Acad Sci U S A 112:11389-94|
|Waning, David L; Mohammad, Khalid S; Reiken, Steven et al. (2015) Excess TGF-? mediates muscle weakness associated with bone metastases in mice. Nat Med 21:1262-1271|
|Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino et al. (2015) Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest 125:1968-78|
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