Glycoursodeoxycholic Acid Alleviates Arterial Thrombosis via Suppressing Diacylglycerol Kinases Activity in Platelet.

Autor:	Yang W; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Feng R; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Peng G; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Wang Z; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Cen M; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China (M.C.)., Jing Y; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Feng W; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Long T; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Liu Y; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Li Z; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Huang K; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.)., Chang G; Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (W.Y., R.F., G.P., Z.W., Y.J., W.F., T.L., Y.L., Z.L, K.H., G.C.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Jun; Vol. 44 (6), pp. 1283-1301. Date of Electronic Publication: 2024 Apr 04.
DOI:	10.1161/ATVBAHA.124.320728
Abstrakt:	Background: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. Methods: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. Results: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction ( P <0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis ( P <0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice ( P <0.05). Conclusions: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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