Background: In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats. Methods: Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks. Results: showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations. Conclusion: Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.
Bien que les travaux portant sur la symptomatologie dépressive de l’enfance soient nombreux, l’affection mélancolique est peu repérée comme une expression psychopathologique avérée chez l’enfant. Les manifestations morbides de l’enfant, regroupant des signes tels que l’autodestruction, l’agitation, la violence, la péjoration de soi, les conduites masochistes, l’affect de tristesse, interrogent cependant les différences fonctionnelles et structurales pouvant exister entre l’expression dépressive et l’état mélancolique chez l’enfant. L’hypothèse avancée ici sera que la mélancolie, ou plutôt le travail de mélancolie , n’appartient pas au seul registre sémiologique de l’adulte, mais qu’elle fait aussi partie du domaine de la clinique de l’enfant. Si, comme l’indique Freud, la mélancolie s’inscrit dans la catégorie des psychonévroses narcissiques, elle ne pourra se réduire à une entité psychopathologique fixée. C’est en termes de mouvement psychique conflictuel et défensif, susceptible de traverser et de perturber passagèrement ou durablement la plupart des organisations mentales, au risque de s’installer en un tableau morbide prévalent et manifeste, que pourrait se comprendre la notion de mélancolie. La dimension de l’enfant, toujours présent dans l’adulte, sera donc ici convoquée.
This study elucidates the possible contribution of mitochondria to the anti‐hypertrophic effects of the direct renin inhibitor aliskiren in post‐infarction heart failure (HF) complicated with diabetes. Diabetes was induced in male Sprague‐Dawley rats by a single injection of streptozotocin. After 7 days, the animals were randomly assigned to 4 groups: sham, HF, sham+aliskiren, and HF+aliskiren. HF was induced by coronary artery ligation for 4 weeks. Results demonstrated that HF reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham‐operated hearts. Mitochondria isolated from post‐infarcted hearts demonstrated a 27% and 38% (both P<0.05) less state 3 and respiratory control index, respectively. In addition, cytochrome c loss from mitochondria was significantly higher in ligated hearts. Heart failure enhanced mitochondrial permeability transition pore (PTP) opening. In addition, HF reduced expression of the major mitochondrial sirtuin, SIRT3 with no effects on SIRT4 and SIRT5, and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations. Thus, aliskiren attenuates post‐infarction remodeling which is associated with its indirect beneficial effects on mitochondria. Supported by Novartis Pharma Corporation.
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