Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

Chun-Jen Huang, Wei-Chieh Huang, Wei-Ting Lin, Lan-Hsin Shu, Joen-Rong Sheu, Oanh-Thi Tran, Chih-Wei Hsia, Thanasekaran Jayakumar, Periyakali Saravana Bhavan, Cheng-Ying Hsieh, Chao-Chien Chang

International journal of molecular sciences 2021 Oct 15

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The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 μM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3β pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

Citation

Chun-Jen Huang, Wei-Chieh Huang, Wei-Ting Lin, Lan-Hsin Shu, Joen-Rong Sheu, Oanh-Thi Tran, Chih-Wei Hsia, Thanasekaran Jayakumar, Periyakali Saravana Bhavan, Cheng-Ying Hsieh, Chao-Chien Chang. Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism. International journal of molecular sciences. 2021 Oct 15;22(20)