KR-62980, a novel PPARγ agonist, inhibits collagen-induced platelet activation and thrombus formation by regulating the GPVI signaling pathway

Abstract

Pathological platelet activation is central to cardiovascular disorders. Glycoprotein VI (GPVI), a pivotal collagen receptor, is a promising antithrombotic target. While earlier studies focused on the downstream effects of peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands, we recently identified the proximal PPAR gamma-Src family kinase (SFK) interaction as a key regulatory node. KR-62980 is a novel non-thiazolidinedione (non-TZD) PPAR gamma modulator designed to minimize traditional TZD-associated adverse effects. Here, we investigated whether KR-62980 operates through this "proximal mechanism." We found that KR-62980 dose-dependently inhibited collagen-induced human platelet aggregation in both washed platelets and platelet-rich plasma. Notably, KR-62980 exhibited a predominant sensitivity toward the collagen-GPVI axis compared to thrombininduced protease-activated receptor signaling. Mechanistically, KR-62980 targeted the top of the GPVI signaling hierarchy by disrupting the physical and functional association between PPAR gamma and SFKs (Lyn and Fyn). This blockade suppressed SFK autophosphorylation and dismantled the LAT signalosome, preventing the recruitment of Gads, SLP-76, Btk, and PLC gamma 2. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPAR gamma-mediated antiplatelet action, regardless of the agonist's chemical structure. In vivo, oral administration of KR-62980 significantly prolonged thrombotic occlusion time in a mouse carotid artery thrombosis model. Importantly, at therapeutic doses, KR-62980 did not significantly affect tail bleeding time, demonstrating a favorable safety profile with a wide therapeutic window. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPAR gamma-mediated antiplatelet action and suggest that KR-62980 is a promising candidate for safe antithrombotic therapy.