ABSTRACT
NEW FINDINGS: What is the central question of this study? Does NADPH oxidase activation mediate cardiac sympathetic nerve denervation and dysfunction in heart failure. What is the main findings and its importance? Cardiac sympathetic nerve terminal density and function were reduced in heart failure after myocardial infarction in rabbits. The NADPH oxidase inhibitor apocynin prevented the reduction in cardiac sympathetic nerve terminal density and function in heart failure. This suggest that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in heart failure. NADPH oxidase may be a potential therapeutic target for cardiac sympathetic denervation and dysfunction in heart failure. ABSTRACT: Congestive heart failure (CHF) is characterized by cardiac sympathetic nerve terminal abnormalities, as evidenced by decreased noradrenaline transporter (NAT) density and cardiac catecholaminergic and tyrosine hydroxylase (TH) profiles. These alterations are associated with increased reactive oxygen species (ROS). NADPH oxidase is a major source of ROS in CHF. In this study, we tested the hypothesis that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in CHF. CHF was produced by myocardial infarction (MI) in rabbits. Rabbits with MI or a sham operation were randomized to orally receive an NADPH oxidase inhibitor, apocynin (6 mg kg-1 day-1 ), or placebo for 30 days. MI rabbits exhibited left ventricular dilatation, systolic dysfunction, and increases in NADPH oxidase activity and 4-hydroxynonenal expression in the remote non-infarcted myocardium, all of which were prevented by treatment with apocynin. Cardiac catecholaminergic histofluorescence profiles and immunostained TH and PGP9.5 expression were decreased, and the decreases were ameliorated by apocynin treatment. NAT, TH and PGP9.5 protein and mRNA expression were reduced and the reduction was mitigated by apocynin treatment. The effects of apocynin were confirmed by utilizing the NADPH oxidase inhibitor diphenyleneiodonium in a separate experiment. In conclusion, the NADPH oxidase inhibitor apocynin attenuated increased myocardial oxidative stress and decreased cardiac sympathetic nerve terminals in CHF after MI in rabbits. These findings suggest that the activation of NADPH oxidase mediates cardiac sympathetic nerve terminal abnormalities in CHF, and the inhibition of NADPH oxidase may be beneficial for the treatment of heart failure.
Subject(s)
Acetophenones/pharmacology , Heart Failure/drug therapy , Heart/drug effects , NADPH Oxidases/antagonists & inhibitors , Sympathetic Nervous System/drug effects , Animals , Ganglia, Sympathetic/drug effects , Ganglia, Sympathetic/metabolism , Heart Failure/metabolism , Male , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Myocardium/metabolism , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Rabbits , Reactive Oxygen Species/metabolism , Sympathetic Nervous System/metabolismABSTRACT
Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase activity and endoplasmic reticulum (ER) stress are increased after myocardial infarction (MI). In this study, we proposed to test whether activation of the NADPH oxidase in the remote non-infarcted myocardium mediates ER stress and left ventricular (LV) remodeling after MI. Rabbits with MI or sham operation were randomly assigned to orally receive an NADPH oxidase inhibitor apocynin or placebo for 30 days. The agents were administered beginning at 1 week after surgery. MI rabbits exhibited decreases in LV fractional shortening, LV ejection fraction and the first derivative of the LV pressure rise, which were abolished by apocynin treatment. NADPH oxidase Nox2 protein and mRNA expressions were increased in the remote non-infarcted myocardium after MI. Immunolabeling further revealed that Nox2 was increased in cardiac myocytes in the remote myocardium. The apocynin treatment prevented increases in the Nox2 expression, NADPH oxidase activity, oxidative stress, myocyte apoptosis and GRP78, CHOP and cleaved caspase 12 protein expression in the remote myocardium. The apocynin treatment also attenuated increases in myocyte diameter and cardiac fibrosis. In cultured H9C2 cardiomyocytes exposed to angiotensin II, an important stimulus for post-MI remodeling, Nox2 knockdown with siRNA significantly inhibited angiotensin II-induced NADPH oxidase activation, reactive oxygen species and GRP78 and CHOP protein expression. We conclude that NADPH oxidase inhibition attenuates increased ER stress in the remote non-infarcted myocardium and LV remodeling late after MI in rabbits. These findings suggest that the activation of NADPH oxidase in the remote non-infarcted myocardium mediates increased ER stress, contributing to myocyte apoptosis and LV remodeling after MI.
Subject(s)
Endoplasmic Reticulum Stress/physiology , Myocardial Infarction/physiopathology , NADPH Oxidases/metabolism , Ventricular Remodeling/physiology , Acetophenones/pharmacology , Angiotensin II/pharmacology , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Heat-Shock Proteins/metabolism , Microscopy, Confocal , Myocardial Infarction/enzymology , Myocardial Infarction/mortality , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/genetics , RNA Interference , Rabbits , Random Allocation , Rats , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Transcription Factor CHOP/metabolism , Vasoconstrictor Agents/pharmacology , Ventricular Remodeling/drug effectsABSTRACT
OBJECTIVE: To study the chemical constituents of Microtropis triflora. METHOD: The compounds were isolated by chromatography on silica gel and Sephadex LH-20. There structures were elucidatedby by chemical methods and spectral analysis. RESULT: Five triterpenoids were isolated and elucidated as friedelin (1), 3-oxo-28-friedelanoic acid (2), 29-hydroxy-3-friedelanone (3), salaspermic acid (4), orthosphenic acid (5). CONCLUSION: Compounds 1-5 are all isolated from M. triflora for the first time.
