| First Author | Dridi H | Year | 2023 |
| Journal | Nat Neurosci | Volume | 26 |
| Issue | 8 | Pages | 1365-1378 |
| PubMed ID | 37429912 | Mgi Jnum | J:362478 |
| Mgi Id | MGI:8159062 | Doi | 10.1038/s41593-023-01377-6 |
| Citation | Dridi H, et al. (2023) Heart failure-induced cognitive dysfunction is mediated by intracellular Ca(2+) leak through ryanodine receptor type 2. Nat Neurosci 26(8):1365-1378 |
| abstractText | 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. |
