Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2
Haikel Dridi, Yang Liu, Steve Reiken, Xiaoping Liu, Elentina K. Argyrousi, Qi Yuan, Marco Miotto, Leah Sittenfeld, Andrei Meddar, Rajesh K. Soni, Ottavio Arancio, Alain Lacampagne, Andrew R. Marks
Abstract
Abstract Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD in HF remains unclear. Here, we show in hippocampal neurons from individuals and mice with HF that the RyR2/intracellular Ca 2+ release channels were subjected to post-translational modification (PTM) and were leaky. RyR2 PTM included protein kinase A phosphorylation, oxidation, nitrosylation and depletion of the stabilizing subunit calstabin2. RyR2 PTM was caused by hyper-adrenergic signaling and activation of the transforming growth factor-beta pathway. HF mice treated with a RyR2 stabilizer drug (S107), beta blocker (propranolol) or transforming growth factor-beta inhibitor (SD-208), or genetically engineered mice resistant to RyR2 Ca 2+ leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca 2+ leak that includes cardiogenic dementia.