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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2
Haikel Dridi1, Yang Liu2, Steven Reiken2
1Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA. dh2756@cumc.columbia.edu.
Insights
Heart failure causes cognitive dysfunction through leaky RyR2 channels in the brain. Treatments targeting RyR2, like stabilizers or beta blockers, can protect against this heart failure-induced cognitive decline.
Area of Science:
- Neuroscience
- Cardiology
- Molecular Biology
Background:
- Cognitive dysfunction (CD) significantly impacts heart failure (HF) patients' quality of life and treatment adherence.
- The role of ryanodine receptor type 2 (RyR2) in HF-associated CD is not well understood.
Purpose of the Study:
- To investigate the involvement of RyR2 in cognitive dysfunction in heart failure.
- To explore the mechanisms underlying RyR2 dysfunction in HF-induced CD.
Main Methods:
- Analysis of hippocampal neurons from human and mouse models of HF.
- Assessment of RyR2 post-translational modifications (PTMs) including phosphorylation, oxidation, and calstabin2 levels.
- Evaluation of therapeutic interventions targeting RyR2 in HF mouse models.
Main Results:
- RyR2 channels in hippocampal neurons from HF individuals and mice exhibit PTMs, leading to intracellular Ca2+ leak.
- Hyper-adrenergic signaling and TGF-beta pathway activation contribute to RyR2 PTMs.
- Treatment with an RyR2 stabilizer (S107), propranolol, or SD-208, and use of RyR2-p.Ser2808Ala mice protected against HF-induced CD.
Conclusions:
- HF-induced cognitive dysfunction is linked to leaky RyR2 channels in the brain.
- RyR2 PTMs driven by hyper-adrenergic signaling and TGF-beta pathway are key mechanisms.
- Targeting RyR2 offers a potential therapeutic strategy for cardiogenic dementia.
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 Ca2+ 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 Ca2+ leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca2+ leak that includes cardiogenic dementia.
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