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

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 remains unclear. Here, we show in hippocampal neurons from patients and mice with HF that the ryanodine receptor type 2 (RyR2)/intracellular Ca 2+ release channels were post-translationally modified (PTM) and leaky. RyR2 PTM was caused by hyper-adrenergic stress and activation of the transforming growth factor (TGF-β) pathway. HF mice treated with either a RyR2 stabilizer drug (S107), beta-blocker (propranolol) or TGF-β inhibitor (SD-208), or mice insensitive RyR2 Ca 2+ leak (RyR2-S2808A), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness that include cardiogenic dementia, and intracellular Ca 2+ leak is a common effector in multiple components of HF.

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Rajesh Soni

LAB HEAD: Haikel Dridi

PROVIDER: PXD042295 | Pride | 2023-08-30

REPOSITORIES: Pride

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

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