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Abstract
Pulmonary hypertension (PH) is a devastating disease characterized by vascular remodeling, resulting in right ventricular failure and death. Dysregulation of energy metabolism is linked to PH pathogenesis. Trimetazidine (TMZ), a selective long-chain 3-ketoacyl coenzyme A thiolase inhibitor, is critical in maintaining energy metabolism. Despite the indicated TMZ’s inhibitory effect on pulmonary vascular remodeling in PH development, the integrated evaluation of the changes in biomolecules, such as metabolites and transcripts, that TMZ induces in the lung and heart tissues is largely unknown in vivo. For an improved understanding of the molecular mechanism involving the effects of TMZ on PH development, we performed a comprehensive analysis of the changes in cardiac metabolites and pulmonary transcripts of SU5416-Hypoxia (Su/Hx) rats treated with TMZ. Metabolomic analysis of the Su/Hx-induced PH hearts demonstrated that TMZ reduced the long-chain fatty acid concentration. Additionally, TMZ alleviated PH degree and excessive strain on the right heart functions in rats with Su/Hx-induced PH. We identified the candidate target genes for TMZ treatment during PH development. Interestingly, the mRNA levels of the fatty acid transporters were substantially downregulated by TMZ administration in the lungs with Su/Hx-induced PH. Notably, TMZ suppressed excessive proliferation of human pulmonary artery smooth muscle cells under hypoxic conditions. Our study suggests that TMZ ameliorates PH development by involving energy metabolism in the lungs and heart.
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Details
1 Chiba University, Department of Respirology, Graduate School of Medicine, Chiba, Japan (GRID:grid.136304.3) (ISNI:0000 0004 0370 1101)
2 University of Toyama, Division of Complex Biosystem Research, Department of Research and Development, Institute of National Medicine, Toyama, Japan (GRID:grid.267346.2) (ISNI:0000 0001 2171 836X); University of Tsukuba, Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), Ibaraki, Japan (GRID:grid.20515.33) (ISNI:0000 0001 2369 4728); AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan (GRID:grid.480536.c) (ISNI:0000 0004 5373 4593)
3 Chiba University, Department of Respirology, Graduate School of Medicine, Chiba, Japan (GRID:grid.136304.3) (ISNI:0000 0004 0370 1101); International University of Health and Welfare, Department of Pulmonary Medicine, School of Medicine, Chiba, Japan (GRID:grid.411731.1) (ISNI:0000 0004 0531 3030)
4 Chiba University, Department of Respirology, Graduate School of Medicine, Chiba, Japan (GRID:grid.136304.3) (ISNI:0000 0004 0370 1101); National Institutes of Biomedical Innovation, National Institutes of Biomedical Innovation, Microbial Research Center for Health and Medicine, Osaka, Japan (GRID:grid.136304.3)
5 University of Toyama, Division of Complex Biosystem Research, Department of Research and Development, Institute of National Medicine, Toyama, Japan (GRID:grid.267346.2) (ISNI:0000 0001 2171 836X)
6 University of Toyama, Section of Host Defences, Institute of Natural Medicine, Toyama, Japan (GRID:grid.267346.2) (ISNI:0000 0001 2171 836X)
7 Chiba University, Department of Respirology, Graduate School of Medicine, Chiba, Japan (GRID:grid.136304.3) (ISNI:0000 0004 0370 1101); Juntendo University, Department of Molecular and Systems Pharmacology, Faculty of Pharmacy, Chiba, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738)