Sulforaphane Attenuates Aldose Reductase-mediated Platelet Dysfunction in High Glucose-stimulated Human platelets via Downregulation of the Src/ROS/p53 Signaling Pathway

Xiaoyan Bi¹Xinhui Huang²Chunmei Zhang¹Xin Zhao¹Junyu Ma¹Mengyao Li¹Xuexun Li¹Bangzhao Zeng¹Rong Li¹Xian Zhang³Fuli Ya^1*

• ¹School of Public Health, Dali University, Dali, China
• ²Huzhou Health Vocational College, Huzhou, China
• ³Dali Bai Autonomous Prefecture People's Hospital, Dali, China

Platelet abnormalities are well-recognized complications of type 2 diabetes mellitus (T2DM). High glucose (HG) increases platelet mitochondrial dysfunction, apoptosis and hyperreactivity in T2DM, which underlie the occurrence of thrombotic events. Sulforaphane (SFN) is a dietary isothiocyanate enriched in cruciferous vegetables and possesses multiple biological activities. This study aimed to explore the efficacy of SFN on platelet dysfunction in HG-stimulated human platelets in vitro. We demonstrated that SFN attenuated HG-induced platelet dysfunction by alleviating mitochondrial dysfunction (manifested as loss of mitochondrial membrane potential; P < 0.001), apoptosis (characterized by increased caspase-9/-3 activation and phosphatidylserine exposure; P < 0.01), and hyperreactivity (evidenced by enhanced aggregation and activation; P < 0.05). Mechanistically, SFN significantly suppressed HG-induced aldose reductase (AR) activity (P < 0.001). Pharmacological inhibition revealed that the beneficial effects of SFN on platelet function are mediated mechanistically through AR downregulation, which attenuates p53 phosphorylation via Src-dependent ROS generation. Collectively, these findings suggest that by inhibiting the Src/ROS/p53 signaling pathway and mitigating AR-mediated platelet dysfunction, SFN may confer significant protection against atherothrombosis during hyperglycemia.