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Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension
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Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension
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Journal Article
Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension
2024
Overview
Background
High levels of lactate are positively associated with prognosis and mortality in pulmonary hypertension (PH). Lactate dehydrogenase A (LDHA) is a key enzyme for the production of lactate. This study is undertaken to investigate the role and molecular mechanisms of lactate and LDHA in PH.
Methods
Lactate levels were measured by a lactate assay kit. LDHA expression and localization were detected by western blot and Immunofluorescence. Proliferation and migration were determined by CCK8, western blot, EdU assay and scratch-wound assay. The right heart catheterization and right heart ultrasound were measured to evaluate cardiopulmonary function.
Results
In vitro, we found that lactate promoted proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in an LDHA-dependent manner. In vivo, we found that LDHA knockdown reduced lactate overaccumulation in the lungs of mice exposed to hypoxia. Furthermore, LDHA knockdown ameliorated hypoxia-induced vascular remodeling and right ventricular dysfunction. In addition, the activation of Akt signaling by hypoxia was suppressed by LDHA knockdown both in vivo and in vitro. The overexpression of Akt reversed the inhibitory effect of LDHA knockdown on proliferation in PASMCs under hypoxia. Finally, LDHA inhibitor attenuated vascular remodeling and right ventricular dysfunction in Sugen/hypoxia mouse PH model, Monocrotaline (MCT)-induced rat PH model and chronic hypoxia-induced mouse PH model.
Conclusions
Thus, LDHA-mediated lactate production promotes pulmonary vascular remodeling in PH by activating Akt signaling pathway, suggesting the potential role of LDHA in regulating the metabolic reprogramming and vascular remodeling in PH.
Publisher
BioMed Central,BioMed Central Ltd,BMC
Subject
/ Animals
/ Biomedical and Life Sciences
/ Complications and side effects
/ Fibrosis
/ Humans
/ Hypertension, Pulmonary - metabolism
/ Hypertension, Pulmonary - pathology
/ Hypertension, Pulmonary - physiopathology
/ L-Lactate Dehydrogenase - metabolism
/ Lactate
/ Lactate Dehydrogenase 5 - metabolism
/ Male
/ Mice
/ Myocytes, Smooth Muscle - metabolism
/ Myocytes, Smooth Muscle - pathology
/ Proto-Oncogene Proteins c-akt - metabolism
/ Pulmonary Artery - metabolism
/ Pulmonary Artery - pathology
/ Rats
