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

Pengyu Zong; Cindy Li; Jianlin Feng; Zhichao Yue; Nicholas Legere; Albert S Yu; Fahad Shah; Adrianna Perez; Zhu Li; Evan Jellison; Yasuo Mori; Barbara Miller; Rajkumar Verma; Bruce Liang; Lixia Yue

doi:10.1016/j.xcrm.2025.101998

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

Cell Rep Med. 2025 Mar 18;6(3):101998. doi: 10.1016/j.xcrm.2025.101998. Epub 2025 Mar 7.

Authors

Pengyu Zong¹, Cindy Li², Jianlin Feng³, Zhichao Yue³, Nicholas Legere⁴, Albert S Yu³, Fahad Shah⁵, Adrianna Perez⁵, Zhu Li⁶, Evan Jellison⁶, Yasuo Mori⁷, Barbara Miller⁸, Rajkumar Verma⁹, Bruce Liang⁵, Lixia Yue¹⁰

Affiliations

¹ Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Cell Biology, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, 337 Mansfield Road, Unit 1272, Storrs, CT 06269, USA. Electronic address: zong@uchc.edu.
² Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Cell Biology, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, 337 Mansfield Road, Unit 1272, Storrs, CT 06269, USA.
³ Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Cell Biology, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA.
⁴ Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Cell Biology, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA.
⁵ Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA.
⁶ Department of Immunology, University of Connecticut School of Medicine (UConn Health), Farmington, 263 Farmington Avenue, CT 06030, USA.
⁷ Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
⁸ Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033, USA.
⁹ Department of Neuroscience, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA.
¹⁰ Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA; Department of Cell Biology, University of Connecticut School of Medicine (UConn Health), 263 Farmington Avenue, Farmington, CT 06030, USA. Electronic address: lyue@uchc.edu.

Abstract

Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe^-/- mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2's pivotal role in mediating hyperlipidemia's detrimental effects on myeloid cells and neurovascular units. Our findings suggest that TRPM2 is a promising therapeutic target for alleviating neurodegenerative diseases exacerbated by hyperlipidemia, such as ischemic stroke. These results also highlight TRPM2 expression in peripheral blood as a potential biomarker for predicting stroke outcomes in hyperlipidemic patients.

Keywords: BBB; TRPM2; blood-brain-barrier damage; endothelial dysfunction; hyperlipidemia; myeloid cell activation; oxLDL; stroke.

MeSH terms

Animals
Apolipoproteins E / deficiency
Disease Models, Animal
Female
Humans
Hyperlipidemias* / complications
Hyperlipidemias* / metabolism
Hyperlipidemias* / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Myeloid Cells* / metabolism
Myeloid Cells* / pathology
TRPM Cation Channels* / genetics
TRPM Cation Channels* / metabolism

Substances

TRPM Cation Channels
TRPM2 protein, mouse
TRPM2 protein, human
Apolipoproteins E

Abstract

MeSH terms

Substances

Grants and funding