5-Methoxytryptophan attenuates postinfarct cardiac injury by controlling oxidative stress and immune activation. (September 2021)

• Record Type: Journal Article
• Authors: Hsu, Wan-Tseng; Tseng, Ya-Hsuan; Jui, Hsiang-Yiang; Kuo, Chen-Chin; Wu, Kenneth K.; Lee, Chii-Ming
• Is Part Of: Journal of molecular and cellular cardiology. Volume 158(2021)
• Page Start: 101
• Page End: 114
• Publication Date: 2021-09
• Subjects: 5-Methoxytryptophan -- Myocardial infarction -- Oxidative stress -- Inflammation -- NADPH oxidase; AAR area at risk -- 5-MTP 5-Methoxytryptophan -- Casp3 caspase-3 -- CCL2 CC motif chemokine ligand 2 -- CCL5 CC motif chemokine ligand 5 -- CL chemiluminescence -- cTnI cardiac troponin I -- CXCL10 CXC motif chemokine ligand 10 -- CXCL2 CXC motif chemokine ligand 2 -- ET-1 endothelin-1 -- IA Infarct area -- IHC immunohistochemical -- IL-1β interleukin-1β -- IP intraperitoneal -- IV intravenous -- LAD left anterior descending coronary artery -- LVEF LV ejection fraction -- LVFS LV fraction shortening -- LVIDd LV internal dimensions at end-diastole -- LVIDs LV internal dimensions at end-systole -- NF-kb nuclear factor-κb -- NOX nicotinamide adenine dinucleotide phosphate oxidase -- ROS reactive oxygen species -- TNF-α tumor necrosis factor-α -- TOMM20 translocase of outer mitochondrial membrane 20 -- Tph1 tryptophan hydroxylase-1 -- TTC triphenyltetrazolium chloride -- TUNEL terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.05.014
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Aims: Myocardial infarction (MI) remains a major cause of heart failure. 5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of L-tryptophan, exerts anti-inflammatory and antifibrotic effects, but MI impairs the biosynthesis of cardiac 5-MTP. Therefore, we evaluated the effect of exogenous 5-MTP administration on rescuing post-MI cardiac injury. Methods and results: After a detailed pharmacokinetic analysis of 5-MTP, Sprague Dawley rats that had undergone left anterior descending coronary artery ligation received intraperitoneal administration of either 17 mg/kg 5-MTP or saline at 0.5 and 24 h after MI. Cardiac systolic function, infarction size, and fibrosis were evaluated using echocardiography, triphenyltetrazolium chloride staining, and Masson trichrome staining, respectively. Myocardial apoptosis was analyzed by staining for caspase-3 and cardiac troponin I. 5-MTP treatment decreased the infarct area and myocardial apoptosis; attenuated systolic dysfunction and left ventricular dilatation; and reduced cardiomyocyte hypertrophy, myocardial fibrosis, and infarct expansion. Crucially, 5-MTP alleviated oxidative stress by preserving mitochondrial antioxidant enzymes and downregulating reactive oxygen species–generating NADPH oxidase isoforms and endothelin-1. Consequently, 5-MTP-treated MI rat hearts exhibited lower levels of chemokines and cytokines, namely interleukin (IL)-1β, IL-18, IL-6, C-C motif chemokine ligand (CCL)-2, and CCL5, accompanied by reduced infiltration of CD11b + cells and CD4 + T cells. Notably, 5-MTP protected against H2 O2 -induced damage in HL-1 cardiomyocytes and human umbilical vein endothelial cells in vitro. Conclusion: 5-MTP prevented post-MI cardiac injury by promoting mitochondrial stabilization and controlling redox imbalance. This cytoprotective effect ameliorated macrophage and T-cell infiltration, thus reducing the infarct size, attenuating fibrosis, and restoring myocardial function. Graphical abstract: Unlabelled Image Highlights: Cardiac 5-MTP biosynthesis is impaired following myocardial infarction (MI). 5-MTP treatment within 24 h of MI improves left ventricular systolic function. 5-MTP administered within 24 h of MI effectively attenuated cardiac inflammation. 5-MTP promotes mitochondrial stabilization and controls redox imbalance. 5-MTP protected against H2 O2 -induced cardiomyocyte and endothelial cell death.