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Cardiovasc Res ; 114(7): 1006-1015, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29579152


Aims: We previously demonstrated that acute ethanol administration protects the heart from ischaemia/reperfusion (I/R) injury thorough activation of aldehyde dehydrogenase 2 (ALDH2). Here, we characterized the role of acetaldehyde, an intermediate product from ethanol metabolism, and its metabolizing enzyme, ALDH2, in an ex vivo model of cardiac I/R injury. Methods and results: We used a combination of homozygous knock-in mice (ALDH2*2), carrying the human inactivating point mutation ALDH2 (E487K), and a direct activator of ALDH2, Alda-1, to investigate the cardiac effect of acetaldehyde. The ALDH2*2 mice have impaired acetaldehyde clearance, recapitulating the human phenotype. Yet, we found a similar infarct size in wild type (WT) and ALDH2*2 mice. Similar to ethanol-induced preconditioning, pre-treatment with 50 µM acetaldehyde increased ALDH2 activity and reduced cardiac injury in hearts of WT mice without affecting cardiac acetaldehyde levels. However, acetaldehyde pre-treatment of hearts of ALDH2*2 mice resulted in a three-fold increase in cardiac acetaldehyde levels and exacerbated I/R injury. Therefore, exogenous acetaldehyde appears to have a bimodal effect in I/R, depending on the ALDH2 genotype. Further supporting an ALDH2 role in cardiac preconditioning, pharmacological ALDH2 inhibition abolished ethanol-induced cardioprotection in hearts of WT mice, whereas a selective activator, Alda-1, protected ALDH2*2 against ethanol-induced cardiotoxicity. Finally, either genetic or pharmacological inhibition of ALDH2 mitigated ischaemic preconditioning. Conclusion: Taken together, our findings suggest that low levels of acetaldehyde are cardioprotective whereas high levels are damaging in an ex vivo model of I/R injury and that ALDH2 is a major, but not the only, regulator of cardiac acetaldehyde levels and protection from I/R.

Acetaldeído/farmacologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Acetaldeído/metabolismo , Acetaldeído/toxicidade , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática , Técnicas de Introdução de Genes , Genótipo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Fenótipo , Mutação Puntual , Ratos , Fatores de Tempo
J Clin Invest ; 123(4): 1492-500, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23524969


Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.

Regulação da Expressão Gênica , Hipotálamo/enzimologia , Iodeto Peroxidase/metabolismo , Hipófise/enzimologia , Tireotropina/genética , Tri-Iodotironina/sangue , Animais , Astrócitos/enzimologia , Composição Corporal , Córtex Cerebral/metabolismo , Ativação Enzimática , Retroalimentação Fisiológica , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Iodeto Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Hipófise/citologia , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiologia , Tireotrofos/enzimologia , Tireotropina/sangue , Hormônio Liberador de Tireotropina , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia