L-棕榈酰肉碱增强纤溶酶和tPA抑制血栓形成。

IF 4.8 3区化学 Q1 CHEMISTRY, MEDICINAL Natural Products and Bioprospecting Pub Date : 2023-11-08 DOI:10.1007/s13659-023-00413-z

Juan Yang, Lina Cha, Yepeng Wang, Quan Zhang, Xiaopeng Tang, Jianlin Shao, Zilei Duan

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摘要

L-棕榈酰肉碱（L-PC）是一种重要的内源性脂肪酸代谢产物。其经典的生物学功能涉及膜分子动力学和脂肪酸的β-氧化的调节。血浆长链酰基肉碱的减少表明与静脉血栓形成有关，这意味着代谢产物具有抗凝血活性，并启发我们研究长链酰基肉毒碱L-PC是否以及如何参与凝血。在这里，我们发现L-PC通过增强纤溶酶和组织纤溶酶原激活剂（tPA）的酶活性来发挥抗凝作用。L-PC与纤溶酶和tPA直接相互作用，平衡解离常数（KD）为6.47 × 10-9和4.46 × 10-9M，显示出高亲和力。在小鼠模型中，L-PC给药显著抑制了FeCl3诱导的动脉血栓形成。它还减轻了短暂性大脑中动脉闭塞（tMCAO）小鼠模型中的脑内血栓形成和炎症。L-PC引起的出血并发症很少。结果表明，L-PC具有增强纤溶酶和tPA的抗血栓作用。

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l-Palmitoylcarnitine potentiates plasmin and tPA to inhibit thrombosis

l-Palmitoylcarnitine (L-PC) is an important endogenous fatty acid metabolite. Its classical biological functions are involved in the regulations of membrane molecular dynamics and the β-oxidation of fatty acids. Decreased plasma long-chain acylcarnitines showed the association of venous thrombosis, implying anticoagulant activity of the metabolites and inspiring us to investigate if and how L-PC, a long-chain acylcarnitine, takes part in coagulation. Here we show that L-PC exerted anti-coagulant effects by potentiating the enzymatic activities of plasmin and tissue plasminogen activator (tPA). L-PC directly interacts with plasmin and tPA with an equilibrium dissociation constant (KD) of 6.47 × 10^–9 and 4.46 × 10^–9 M, respectively, showing high affinities. In mouse model, L-PC administration significantly inhibited FeCl₃-induced arterial thrombosis. It also mitigated intracerebral thrombosis and inflammation in a transient middle cerebral artery occlusion (tMCAO) mouse model. L-PC induced little bleeding complications. The results show that L-PC has anti-thrombotic function by potentiating plasmin and tPA.