LDHA mediated degradation of extracellular matrix is a potential target for the treatment of aortic dissection.

Autor: Wu X; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China., Ye J; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China., Cai W; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China., Yang X; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Provincial Special Reserve Talents Laboratory, Fuzhou, China., Zou Q; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China., Lin J; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China., Zheng H; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Provincial Special Reserve Talents Laboratory, Fuzhou, China; Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China., Wang C; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China., Chen L; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Provincial Special Reserve Talents Laboratory, Fuzhou, China; Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, China; Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China. Electronic address: chenliangwan@tom.com., Li Y; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Provincial Special Reserve Talents Laboratory, Fuzhou, China; The School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China. Electronic address: liyumei@fjmu.edu.cn.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2022 Feb; Vol. 176, pp. 106051. Date of Electronic Publication: 2021 Dec 30.
DOI: 10.1016/j.phrs.2021.106051
Abstrakt: Aortic dissection (AD) is a disease with high mortality and lacks effective drug treatment. Recent studies have shown that the development of AD is closely related to glucose metabolism. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme and plays an important role in cardiovascular disease. However, the role of LDHA in the progression of AD remains to be elucidated. Here, we found that the level of LDHA was significantly elevated in AD patients and the mouse model established by BAPN combined with Ang II. In vitro, the knockdown of LDHA reduced the growth of human aortic vascular smooth muscle cells (HAVSMCs), glucose consumption, and lactate production induced by PDGF-BB. The overexpression of LDHA in HAVSMCs promoted the transformation of HAVSMCs from contractile phenotype to synthetic phenotype, and increased the expression of MMP2/9. Mechanistically, LDHA promoted MMP2/9 expression through the LDHA-NDRG3-ERK1/2-MMP2/9 pathway. In vivo, Oxamate, LDH and lactate inhibitor, reduced the degradation of elastic fibers and collagen deposition, inhibited the phenotypic transformation of HAVSMCs from contractile phenotype to synthetic phenotype, reduced the expression of NDRG3, p-ERK1/2, and MMP2/9, and delayed the progression of AD. To sum up, the increase of LDHA promotes the production of MMP2/9, stimulates the degradation of extracellular matrix (ECM), and promoted the transformation of HAVSMCs from contractile phenotype to synthetic phenotype. Oxamate reduced the progression of AD in mice. LDHA may be a therapeutic target for AD.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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