Enhanced STIM1 expression drives platelet hyperactivity in diabetes

Abstract

Stromal interaction molecule 1 (STIM1), a key regulator of calcium signaling located in the endoplasmic reticulum, is crucial for platelet function. While elevated STIM1 expression is observed in platelets from diabetic patients, its role in diabetes-induced platelet hyperreactivity remains unclear. In this study, we found a positive correlation between STIM1 expression and agonist-induced platelet aggregation in platelets from patients with type 2 diabetes mellitus (T2DM). Platelets with high STIM1 expression exhibited enhanced aggregation, P-selectin release, integrin αIIbβ3 activation, spreading, and clot retraction compared to those with low STIM1 expression. Similar findings were observed in db/db mice. Furthermore, the store-operated calcium entry channel inhibitor CM4620 demonstrated superior antiplatelet and antithrombotic efficacy compared to aspirin in both db/db mice and patients with T2DM. Our results suggest that elevated STIM1 expression contributes to enhanced platelet reactivity in diabetes, and targeting STIM1 may offer a promising novel therapeutic approach for thrombosis prevention in this patient population.