l-Palmitoylcarnitine potentiates plasmin and tPA to inhibit thrombosis

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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Abstract

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.

Graphical Abstract

Abstract Image

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L-棕榈酰肉碱增强纤溶酶和tPA抑制血栓形成。

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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来源期刊

Natural Products and Bioprospecting CHEMISTRY, MEDICINAL-

CiteScore

8.30

自引率

2.10%

发文量

审稿时长

13 weeks

期刊介绍： Natural Products and Bioprospecting serves as an international forum for essential research on natural products and focuses on, but is not limited to, the following aspects: Natural products: isolation and structure elucidation Natural products: synthesis Biological evaluation of biologically active natural products Bioorganic and medicinal chemistry Biosynthesis and microbiological transformation Fermentation and plant tissue cultures Bioprospecting of natural products from natural resources All research articles published in this journal have undergone rigorous peer review. In addition to original research articles, Natural Products and Bioprospecting publishes reviews and short communications, aiming to rapidly disseminate the research results of timely interest, and comprehensive reviews of emerging topics in all the areas of natural products. It is also an open access journal, which provides free access to its articles to anyone, anywhere.