Work

Mechanistic insights into PPARγ's role in suppressing collagen-driven platelet activation

Year: 2025

Type: article

Abstract: Aims Platelets, despite being anucleate, express peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor implicated in regulating platelet activation. While previous studies suggested that PPARγ ligands inhibit collagen-induced platelet activation by modulating downstream glycoprotein VI (GPVI) signaling without affecting Syk, the upstream regulatory mechanisms remain unclear. This study aimed to determine whether PPARγ ligands modulate Src family kinase (SFK)–dependent signaling, particularly involving Lyn and Fyn, during early GPVI-mediated platelet activation. Materials and methods Washed human platelets were pretreated with rosiglitazone or 15-deoxy-Δ12,14-prostaglandin J₂ (15d-PGJ₂) and stimulated with collagen or the GPVI-selective agonist collagen-related peptide–XL (CRP-XL). Lyn, Fyn, Fc receptor γ-chain (FcRγ), Syk, and downstream components were analyzed by immunoprecipitation and immunoblotting. Platelet aggregation, GPIb–von Willebrand factor (vWF)–mediated signaling, and PKA-dependent VASP phosphorylation were assessed. GW9662 was used to confirm PPARγ dependency. Key findings PPARγ was detected within a proximal GPVI signaling complex containing GPVI, Lyn, Fyn, FcRγ, and Syk. Rosiglitazone and 15d-PGJ 2 disrupted PPARγ association with this complex and reduced Lyn (Tyr397) and Fyn (Tyr420) phosphorylation, leading to decreased FcRγ phosphorylation and impaired Syk recruitment. These effects, along with reduced LAT, Vav1, Btk, and PLCγ2 phosphorylation, were reversed by the PPARγ antagonist GW9662. PPARγ ligands also attenuated Lyn- and Syk-dependent signaling triggered by the GPIb–vWF pathway and suppressed CRP-XL-induced signaling even under α IIb β 3 blockade. Significance These findings identify PPARγ as a regulator of early platelet activation by targeting both Lyn- and Fyn-dependent proximal GPVI signaling and highlight PPARγ ligands as potential dual-purpose therapeutics with antithrombotic benefits alongside their metabolic actions.

Source: Life Sciences

DOI: 10.1016/j.lfs.2025.124138

Authors: Su Bin Wang, Eun Bee Oh, Solee Kim, Jisue Sohn, Taeryeong Kim, Tong-Shin Chang

Institutions: Ewha Womans University, Seoul National University

Language: English

Topic: Platelet Disorders and Treatments

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,810