Ischemic heart disease and stroke are the leading causes of mortality worldwide. One of the pathological features of atherosclerosis is the formation of foam cells after macrophages take up oxidized low-density lipoprotein and become overloaded with cholesterol. These fat-filled macrophages can narrow blood vessels and cause heart disease.

Now, researchers describe how the protein, transient receptor potential melastatin 2 (TRPM2), plays a critical role in atherogenesis. And, how deleting TRPM2 could potentially prevent heart attacks and strokes in humans.

The work is published in Nature Cardiovascular Research, in the paper, “TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2–CD36 inflammatory axis in macrophages.”

As a chronic inflammatory disease of the vessel wall, atherosclerosis is closely associated with oxidative stress conditions. TRPM2 is an oxidative stress-activated calcium-permeable ion channel. TRPM2-mediated calcium signaling has been shown to be involved in various cellular functions including inflammatory cytokine production. As oxidative stress is a prominent feature of atherosclerosis, the researchers of the current study hypothesized that TRPM2 plays a critical role in the development and progression of atherosclerosis.

Their findings show that TRPM2 is activated by inflammation. It signals macrophages to start eating fat. Since inflammation of the blood vessels is one of the primary causes of atherosclerosis, TRPM2 gets activated quite a bit. All that TRPM2 activation pushes macrophage activity, which leads to more foamy macrophages and potentially more inflamed arteries.

More specifically, the team shows that both global and macrophage-specific TRPM2 deletions protect Apoe−/− mice against high-fat diet-induced atherosclerosis. This is characterized by reduced atherosclerotic lesions, decreased macrophage burden, and suppressed inflammasome activation in the vessel walls. The Apoe−/− mouse model is well established for the study of human atherosclerosis. These mice are prone to atherosclerosis.

The research team went on to show that TRPM2 deficiency reduces oxidized low-density lipoprotein uptake by macrophages, thereby minimizing macrophage infiltration, foam cell formation, and inflammatory responses.

Activation of the oxidized low-density lipoprotein receptor CD36 induces TRPM2 activity and vice versa. In cultured macrophages, they showed, TRPM2 is activated by the CD36 ligands oxidized low-density lipoprotein and thrombospondin-1 (TSP1).

Further, deleting TRPM2, or inhibiting TRPM2 activity, suppresses the activation of the CD36 signaling cascade induced by oxidized low-density lipoprotein and TSP1.

The way that TRPM2 activated macrophage activity was surprising, said Lixia Yue, PhD, associate professor in the department of cell biology at the University of Connecticut Health. “They form a vicious cycle promoting the development of atherosclerosis,” Yue said.

This study reveals an important mechanism underlying atherogenesis, and suggests TRPM2 as a promising target for developing more effective therapies for atherosclerosis. Now the team is looking at whether increased TRPM2 expression in monocytes (precursors of macrophages) in the blood correlates with severity of cardiovascular disease in humans. If there is a correlation, they can use TRPM2 as a biomarker for predicting the presence of atherosclerosis in human patients, and ultimately, for predicting the risk of developing heart attack and stroke, the two most common complications of atherosclerosis.

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