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Adenosine signaling in the habenula: a depression-myocardial infarction nexus
Lei Zhang1, Mengge Chu2, Cailing Ji2
1Renmin Hospital of Wuhan University, College of Chemistry and Molecular Sciences, Department of Cardiology, Institute of Molecular Medicine, School of Computer Science, Wuhan University, Wuhan 430072, China; Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha 410082, China.
Insights
Depression elevates myocardial infarction risk via brain adenosine. A novel nanosensor revealed elevated brain adenosine in mice, triggering inflammation and heart damage, which fluoxetine treatment reversed.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Pharmacology
Background:
- Depression is linked to increased myocardial infarction risk, but mechanisms are unclear.
- Adenosine, a neuromodulator, is implicated in both depression and cardiovascular disease.
- Understanding adenosine's role is crucial for linking these conditions.
Purpose of the Study:
- To investigate the mechanistic link between depression and myocardial infarction.
- To develop and utilize a novel adenosine-responsive nanosensor for in vivo brain imaging.
- To explore adenosine's role in neuroinflammation and subsequent cardiac injury.
Main Methods:
- Development of a sensitive adenosine-responsive nanosensor for in vivo brain imaging.
- Assessment of adenosine levels in the habenula of mouse models with depressive-like behavior and myocardial infarction.
- Analysis of microglial activation, pro-inflammatory cytokine release, and downstream signaling pathways (JAK1-STAT1-RIPK1-caspase-8).
- Evaluation of fluoxetine treatment effects on adenosine levels and myocardial damage.
Main Results:
- A marked elevation of adenosine levels was observed in the habenula of affected mouse models.
- Accumulated adenosine activated microglia, leading to neuroinflammation and peripheral inflammation.
- Neuroinflammation triggered cardiomyocyte injury via the JAK1-STAT1-RIPK1-caspase-8 pathway.
- Fluoxetine treatment reduced brain adenosine accumulation and alleviated myocardial damage.
Conclusions:
- Elevated brain adenosine is a key mechanistic link between depression and myocardial infarction.
- Adenosine-induced neuroinflammation contributes to cardiac injury.
- Targeting brain adenosine may offer a therapeutic strategy for comorbid depression and cardiovascular disease.
Abstract:
Depression has been closely associated with an elevated risk of myocardial infarction, yet the underlying mechanistic link remains unclear. Adenosine, a neuromodulator implicated in both depression and cardiovascular diseases, is believed to play a critical role in this connection. Here, we present a highly sensitive adenosine-responsive nanosensor capable of in vivo imaging of adenosine levels in the brain. Using this nanosensor, we identified a marked elevation of adenosine levels in the habenula of mouse models exhibiting both depressive-like behavior and myocardial infarction. Mechanistically, we found that accumulated adenosine activates microglia, leading to the release of pro-inflammatory cytokines and subsequent neuroinflammation. This neuroinflammatory response appears to trigger peripheral inflammation, ultimately activating the JAK1-STAT1-RIPK1-caspase-8 signaling pathway in cardiomyocytes and exacerbating myocardial injury. Importantly, treatment with the antidepressant fluoxetine significantly reduced adenosine accumulation in the brain, as detected by the nanosensor, and simultaneously alleviated myocardial damage. This innovative approach to imaging adenosine in the brain offers fresh insights into the relationship between depression and myocardial infarction.
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