Abstract
Thrombosis is a general pathological phenomenon during severe disturbances to homeostasis, which plays an essential role in cardiovascular and cerebrovascular diseases. Leonurine (LEO), isolated from Leonurus japonicus Houtt, showes a crucial role in anticoagulation and vasodilatation. However, the properties and therapeutic mechanisms of this effect have not yet been systematically elucidated. Therefore, the antithrombotic effect of LEO was investigated in this study. Hematoxylin-Eosin staining was used to detect the thrombosis of zebrafish tail. Fluorescence probe was used to detect the reactive oxygen species. The biochemical indexes related to oxidative stress (lactate dehydrogenase, malondialdehyde, superoxide dismutase and glutathione) and vasodilator factor (endothelin-1 and nitric oxide) were analyzed by specific commercial assay kits. Besides, we detected the expression of related genes (fga, fgb, fgg, pkcα, pkcβ, vwf, f2) and proteins (PI3K, phospho-PI3K, Akt, phospho-Akt, ERK, phospho-ERK FIB) related to the anticoagulation and fibrinolytic system by quantitative reverse transcription and western blot. Beyond that, metabolomic analyses were carried out to identify the expressions of metabolites associated with the anti-thrombosis mechanism of LEO. Our in vivo experimental results showed that LEO could improve the oxidative stress injury, abnormal platelet aggregation and coagulation dysfunction induced by adrenalin hydrochloride. Moreover, LEO restored the modulation of amino acids and inositol metabolites which are reported to alleviate the thrombus formation. Collectively, LEO attenuates adrenalin hydrochloride-induced thrombosis partly via modulating oxidative stress, coagulation cascade and platelet activation and amino acid and inositol metabolites.
Highlights
The aging population and its accompanying increase in vascular pathology, diet and lifestyle changes have led to an increase in the global incidence of cardiovascular disease (CAD)
These results showed that the control group, Adrenalin hydrochloride (AH) group, and LEO group had a significant tendency towards separation, indicating that the metabolism of zebrafish changed significantly after modeling, and LEO intervention had an effect on these metabolites
The results showed that Reactive oxygen species (ROS), lactate dehydrogenase (LDH), and MDA levels were increased significantly, the superoxide dismutase (SOD) and GSH were significantly decreased in AH group, indicating that AH could induce oxidative stress damage in zebrafish in vivo while LEO intervention can dramatically alleviate the oxidative damage
Summary
The aging population and its accompanying increase in vascular pathology, diet and lifestyle changes have led to an increase in the global incidence of cardiovascular disease (CAD). The most commonly antithrombotic drugs used in clinical include anticoagulants (warfarin and heparin), antiplatelet agents (aspirin, clopidogrel and GPIIb–IIIa inhibitors), and thrombolytic drugs (reteplase and tenecteplase) These drugs are usually with single target and irreversible inhibition, which may bring out adverse effects, such as resistant, intolerant, allergy, “aspirin resistance” and bleeding complications during the treatment of complex diseases (Scarborough et al, 1999; Thebault et al, 1999; Wong et al, 2004; Gasparyan et al, 2008; Uchiyama, 2011; Angiolillo, 2012; Di Minno et al, 2012). We investigated the antithrombotic effect and mechanism of LEO on AH-induced thrombosis in zebrafish from multiple perspectives, including antioxidant damage, antiplatelet activation, and anticoagulation cascade reaction. The antithrombotic mechanism of LEO might be related to inhibite oxidative stress, inhibite coagulation cascade reaction, and alter of amino acid and other substances metabolism
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