RESUMEN
BACKGROUND: Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply. METHODS AND RESULTS: To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was prevented by parallel ANT1 overexpression, however, and left ventricular function remarkably improved. The ANT1 overexpression led to a reduction in fibrosis and an improvement in cardiac tissue architecture. Consequently, the survival rate of ANT/REN rats was enhanced. Further investigations into the cardioprotective mechanism of ANT1 overexpression revealed improved mitochondrial structure and function and significantly reduced apoptosis in ANT/REN rats, shown by lowered cytosolic/mitochondrial cytochrome c ratio, reduced caspase 3 level, and prevented DNA degradation. CONCLUSIONS: Myocardial ANT1 overexpression protects against hypertension-induced cardiac pathology. Thus, the improvement in mitochondrial function may be a basic principle for new strategies in treating heart disease.
Asunto(s)
Translocador 1 del Nucleótido Adenina/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Cardiopatías/prevención & control , Hipertensión/complicaciones , Mitocondrias Cardíacas/metabolismo , Translocasas Mitocondriales de ADP y ATP/metabolismo , Translocador 1 del Nucleótido Adenina/genética , Animales , Animales Modificados Genéticamente , Apoptosis , Transporte Biológico/fisiología , Caspasa 3/metabolismo , Citocromos c/metabolismo , Daño del ADN , Regulación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Cardiopatías/etiología , Cardiopatías/patología , Cardiopatías/fisiopatología , Hipertensión/fisiopatología , Translocasas Mitocondriales de ADP y ATP/genética , Ratas , Ratas Sprague-Dawley , Renina/genética , Renina/metabolismo , Tasa de SupervivenciaRESUMEN
The maximal liver function capacity (LiMAx) test, a novel 13C-methacetin breath test, has proven clinical validity in determining hepatic metabolic capacity. In contrast to prior 13C-methacetin breath test protocols, the LiMAx test is performed by intravenous body-weight-adjusted substrate administration. Furthermore, the DOB kinetics (delta over baseline of the time-dependent exhaled 13CO2/12CO2 ratio) are measured online at the bedside with a high time resolution in order to determine the maximum DOB. The aim of this study was to analyze the recorded DOB kinetics in a large population for further refinement of the test protocol. Two new methods of kinetic analysis are proposed in this article: the time dependency of the DOB kinetics and the time interval until half of the DOB maximum. A total of 10 100 LiMAx tests on 8483 patients performed during routine clinics at eight centers were available. The kinetic analysis revealed a specific pattern of DOB kinetics depending upon LiMAx result. In addition, potential co-factors for DOB kinetics, such as weight, height, gender and age, were analyzed, yielding a potential influence of gender and smoking behavior. Both the specific patterns and the proposed kinetic analysis have the potential to further improve the sensitivity and specificity of the test and its clinical applicability by shortening its duration.