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1.
Int J Mol Sci ; 22(11)2021 May 30.
Article in English | MEDLINE | ID: mdl-34070749

ABSTRACT

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE-/- mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Atherosclerosis/drug therapy , Diminazene/analogs & derivatives , Fatty Liver/drug therapy , Plaque, Atherosclerotic/drug therapy , Taurine/biosynthesis , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/etiology , Atherosclerosis/genetics , Atherosclerosis/pathology , Diet, High-Fat , Diminazene/pharmacology , Disease Models, Animal , Fatty Liver/etiology , Fatty Liver/genetics , Fatty Liver/pathology , Female , Gene Expression Regulation , Humans , Liver/drug effects , Liver/metabolism , Liver/pathology , Macrophage Activation , Macrophages/drug effects , Macrophages/metabolism , Macrophages/pathology , Mesenteric Arteries/drug effects , Mesenteric Arteries/metabolism , Mesenteric Arteries/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout, ApoE , Peptide Fragments/genetics , Peptide Fragments/metabolism , Plaque, Atherosclerotic/etiology , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/pathology , THP-1 Cells , Taurine/agonists
2.
J Pharmacol Exp Ther ; 342(1): 61-70, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22473615

ABSTRACT

Taurine acts as a partial agonist at the glycine receptor (GlyR) in some brain regions such as the hippocampus, striatum, and nucleus accumbens. Ethanol, volatile anesthetics, and inhaled drugs of abuse are all known positive allosteric modulators of GlyRs, but their effects on taurine-activated GlyRs remain poorly understood, especially their effects on the high concentrations of taurine likely to be found after synaptic release. Two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes was used to compare the enhancing effects of ethanol, anesthetics, and inhalants on human homomeric α1-GlyR activated by saturating concentrations of glycine versus taurine. Allosteric modulators had negligible effects on glycine-activated GlyR while potentiating taurine-activated currents. In addition, inhaled anesthetics markedly enhanced desensitization rates of taurine- but not glycine-activated receptors. Our findings suggest that ethanol, volatile anesthetics, and inhalants differentially affect the time courses of synaptic events at GlyR, depending on whether the receptor is activated by a full or partial agonist.


Subject(s)
Receptors, Glycine/agonists , Allosteric Regulation/drug effects , Anesthetics/agonists , Anesthetics/pharmacology , Animals , Drug Partial Agonism , Ethanol/agonists , Ethanol/pharmacology , Glycine/agonists , Glycine/pharmacology , Oocytes/drug effects , Oocytes/metabolism , Receptors, Glycine/metabolism , Taurine/agonists , Taurine/pharmacology , Xenopus laevis/metabolism
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