RESUMEN
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.
Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , Aterosclerosis/tratamiento farmacológico , Diminazeno/análogos & derivados , Hígado Graso/tratamiento farmacológico , Placa Aterosclerótica/tratamiento farmacológico , Taurina/biosíntesis , Angiotensina I/genética , Angiotensina I/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/etiología , Aterosclerosis/genética , Aterosclerosis/patología , Dieta Alta en Grasa , Diminazeno/farmacología , Modelos Animales de Enfermedad , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/patología , Femenino , Regulación de la Expresión Génica , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Arterias Mesentéricas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Células THP-1 , Taurina/agonistasRESUMEN
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.
