Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2

• Published in: Nature neuroscience 2023-08, Vol.26 (8), p.1365-1378
• Main Authors: Dridi, Haikel, Liu, Yang, Reiken, Steven, Liu, Xiaoping, Argyrousi, Elentina K., Yuan, Qi, Miotto, Marco C., Sittenfeld, Leah, Meddar, Andrei, Soni, Rajesh Kumar, Arancio, Ottavio, Lacampagne, Alain, Marks, Andrew R.
• Format: Article
• Language: English
• Subjects: 13; 14; 14/19; 59; 631/45/269/1146; 631/80/304; 692/699/375/1370; 82; 82/80; 96; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Calcium (intracellular); Calcium channels; Calcium ions; Calcium release channels; Cardiac muscle; Cardiology and cardiovascular system; Channels; Cognitive ability; Cognitive Sciences; Congestive heart failure; Dementia disorders; Genetic engineering; Growth factors; Heart diseases; Heart failure; Hippocampus; Human health and pathology; Intracellular; Kinases; Leak channels; Life Sciences; Neurobiology; Neurons; Neurons and Cognition; Neurosciences; Oxidation; Phosphorylation; Post-translation; Propranolol; Protein kinase A; Quality of life; Receptors; Ryanodine receptors; Transforming growth factor-b
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-023-01377-6

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. identified a mechanism for cognitive dysfunction after heart failure in which hyper-adrenergic signaling and transforming growth factor-beta activation induced Ca 2+ leak by RyR2 channels in hippocampal neurons.