TRPM2 overactivation drives hyperlipidemia-induced dysfunction of myeloid cells and neurovascular units

Area of Science:

• Biomedical Science
• Neuroscience
• Cardiovascular Science

Background:

• Hyperlipidemia is a major risk factor for various diseases, including stroke.
• The transient receptor potential channel melastatin 2 (TRPM2) is implicated in cellular dysfunction relevant to cardiovascular and neurological conditions.
• TRPM2's role in hyperlipidemia-associated diseases requires further elucidation.

Purpose of the Study:

• To investigate the role of TRPM2 in hyperlipidemia-induced exacerbation of ischemic brain injury.
• To determine if TRPM2 is a viable therapeutic target for stroke in hyperlipidemic individuals.

Main Methods:

• Correlation analysis of TRPM2 expression in human leukocytes with plasma lipid levels.
• Utilizing Apoe knockout mice to model hyperlipidemia and ischemic brain injury.
• Employing global, myeloid, and endothelial TRPM2 knockout strategies and pharmacological inhibition of TRPM2.

Main Results:

• TRPM2 expression in human peripheral leukocytes significantly correlates with plasma lipid levels.
• TRPM2 knockout or inhibition in mice abolished hyperlipidemia-induced worsening of ischemic brain injury.
• TRPM2 mediates hyperlipidemia's detrimental effects on myeloid cells and the neurovascular unit during ischemia.

Conclusions:

• TRPM2 overactivity, driven by hyperlipidemia, contributes to cellular dysfunction during ischemic events.
• TRPM2 is a promising therapeutic target for neurodegenerative diseases, particularly ischemic stroke, in hyperlipidemic patients.
• TRPM2 expression in peripheral blood may serve as a biomarker for predicting stroke outcomes.