Targeting Trem2 Signaling as a Potential Therapeutic Strategy for HFpEF

Trem2 is a transmembrane receptor predominantly expressed in myeloid cells, specifically in monocytes, macrophages, and microglia. In recent years, the Trem2 receptor has been recognized as a significant immune signaling hub activated by pathological conditions. It plays a role in detecting and facilitating tissue damage, limiting its propagation. Trem2-expressing macrophages have recently drawn attention for their role in multiple cardiometabolic diseases. Chronic inflammation is a significant contributor to cardiac dysfunction in heart failure with preserved ejection fraction (HFpEF). Our previous studies showed that circulating soluble Trem2 is increased in mice and humans with HFpEF. Using Trem2 -/- mice, we showed that loss of Trem2 worsens cardiac remodeling and diastolic function in response to DOCA-salt (deoxycorticosterone acetate)-salt. The present study aims to determine whether enhancing Trem2 signaling is a potential therapeutic option for HFpEF. To do this, we chose to inhibit SHIP1, which is a downstream inhibitor of Trem2 signaling. TAD32 [3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine] is a novel small molecule SHIP1 inhibitor that inhibits Trem2 signaling by competing with SYK at DAP12. For these studies, we first determined the IC50 of the TAD-32 inhibitor by performing in vitro experiments using bone marrow-derived macrophages (BMDMs) from Mice. We treated the BMDMs with 0.0,3.3,10.0, and 30.0 µM TAD32 and incubated for 24 hrs. After 24 hours, the viability of cells (% of Live cells) was determined. The TAD-32 inhibitor IC50 value was determined to be 15.37 µM. After determining the IC50 value, we further performed concentration-dependent inhibition using the TAD32 inhibitor on the Trem2 pathway in BMDMs. Additional studies are needed to know if Trem2 agonism using TAD32 will reduce the cardiac dysfunction associated with HFpEF. AHA-CSA-4187940, NIH-R01HL161212 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.