Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through remodeled ryanodine receptor type 2, which can be prevented by the RyR2 stabilizer S107.
Does pharmacological stabilization of RyR2 channels prevent cognitive dysfunction in a mouse model of heart failure?
Heart failure-induced cognitive dysfunction is mediated by intracellular calcium leak through RyR2 channels, which can be prevented by pharmacological stabilization of the channel.
Absolute Event Rate: 0.19% vs 0.01%
p-value: p=<0.05
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.
Dridi et al. (Mon,) conducted a other in Heart failure (n=13). S107 (Rycal drug), propranolol, SD-208 vs. Untreated heart failure / SHAM was evaluated on RyR2 open probability (Po) in human hippocampi (p=<0.05). Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through remodeled ryanodine receptor type 2, which can be prevented by the RyR2 stabilizer S107.