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TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages
Pengyu Zong1, Jianlin Feng1, Zhichao Yue1
1Department of Cell Biology, Calhoun Cardiology Center, University of Connecticut School of Medicine (UConn Health), Farmington, CT 06030, USA.
Insights
Oxidative stress-activated TRPM2 channels are crucial in atherosclerosis development. Blocking TRPM2 reduces macrophage foam cell formation and inflammation, offering a potential therapeutic target for this disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Immunology
Background:
- Atherosclerosis, a leading cause of death, involves macrophage infiltration and foam cell formation.
- The precise mechanisms driving these pathological processes are not fully understood.
Purpose of the Study:
- To investigate the role of oxidative stress-activated Ca2+-permeable transient receptor potential melastatin 2 (TRPM2) in atherosclerosis.
- To elucidate the molecular mechanisms linking TRPM2 to macrophage function and atherogenesis.
Main Methods:
- Utilized global and macrophage-specific Trpm2 deletion in Apoe-/- mouse models of atherosclerosis.
- Investigated oxidized low-density lipoprotein (oxLDL) uptake, macrophage infiltration, and foam cell formation in vitro and in vivo.
- Examined the interaction between TRPM2 and the oxLDL receptor CD36.
Main Results:
- Trpm2 deletion significantly protected against atherosclerosis development in mice.
- Trpm2 deficiency reduced macrophage uptake of oxLDL, thereby decreasing foam cell formation and inflammatory responses.
- TRPM2 and CD36 mutually regulate each other's activity, with oxLDL and TSP1 activating TRPM2 via CD36.
Conclusions:
- The TRPM2-CD36 axis represents a key molecular mechanism in atherogenesis.
- TRPM2 plays a critical role in regulating macrophage responses to oxLDL.
- TRPM2 emerges as a promising therapeutic target for treating atherosclerosis.
Abstract:
Atherosclerosis is the major cause of ischemic heart disease and stroke, the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable transient receptor potential melastatin 2 (TRPM2) plays a critical role in atherogenesis. Both global and macrophage-specific Trpm2 deletion protect Apoe mice against atherosclerosis. Trpm2 deficiency reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, thereby minimizing macrophage infiltration, foam cell formation and inflammatory responses. Activation of the oxLDL receptor CD36 induces TRPM2 activity, and vice versa. In cultured macrophages, TRPM2 is activated by CD36 ligands oxLDL and thrombospondin-1 (TSP1), and deleting Trpm2 or inhibiting TRPM2 activity suppresses the activation of CD36 signaling cascade induced by oxLDL and TSP1. Our findings establish the TRPM2-CD36 axis as a molecular mechanism underlying atherogenesis, and suggest TRPM2 as a potential therapeutic target for atherosclerosis.
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