Involvement of Piezo 1 in inhibition of shear-induced platelet activation and arterial thrombosis by ginsenoside Rb1

Authors:

Yilin Wang, Lu Liu, Jia Li, Yue You, Shunli Xiao, Jiantao Feng, Xiaojie Yin, Fulong Liao, Yun You

Keywords:

Shear-induced platelet activation and aggregation; SIPA; Piezo 1; arterial thrombosis; calcium channel; mechanosensitive; ginsenoside Rb1;

Abstract:

Background and Purpose: Shear-induced platelet activation and aggregation (SIPA) play crucial roles in arterial thrombosis. Piezo1 is a mechanosensitive calcium channel that promotes platelet hyperactivation under pathological high-shear conditions. This study explores the function of platelet Piezo1 in SIPA and arterial thrombosis, and the inhibitory effects and mechanisms of ginsenoside Rb1 on these processes.

Experimental Approach: Transgenic mice with platelet-specific Piezo1 deficiency (Piezo1ΔPlt) were used to elucidate the role of platelet Piezo1 in SIPA and arterial thrombosis. A microfluidic channel system was employed to assess platelet aggregation, calcium influx, calpain activity, talin cleavage, integrin αIIbβ3 activation and P-selectin expression under shear flow. Cellular thermal shift assay was used to determine binding between Rb1 and Piezo1. Folts-like model in mice was used to evaluate antithrombotic effects of Rb1.

Key Results: Piezo1 deficiency in platelets reduced platelet activation and aggregation induced by a high shear rate of 4000 s−1 and attenuated arterial thrombosis induced by Folts-like mouse model. Rb1 inhibited SIPA with an IC50 of 10.8 μM. Rb1 inhibited shear-induced Ca2+-dependent platelet activation and aggregation, as well as thrombus formation in Folts-like model in Piezo1fl/fl mice. Rb1 significantly improved thermal stability of Piezo1 in platelets by binding to Piezo1. Treatment of Piezo1ΔPlt mice with Rb1 did not exhibit further inhibitory effects on SIPA and thrombosis.

Conclusion and Implications: Platelet Piezo1 is essential for SIPA and arterial thrombosis induced by high shear. Rb1 exerted anti-platelet and anti-thrombotic effects at high shear rates via Piezo1 channels, providing a potential candidate as antiplatelet therapeutic agent.

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