Abstract 236: Cardiac Overexpression of Thioredoxin-1 Delays Mitochondrial Damage and Prolongs Survival in Septic Mice
Introduction: Current evidence suggests a main role of thioredoxin-1 (trx1) in the protection against oxidative stress. However, it is unknown yet a putative role of trx1 in the regulation of contractility and mitochondrial function, dynamics and biogenesis in sepsis-induced myocardial dysfunction in which oxidative stress is an underlying cause.
Methods: Transgenic male mice (Tg-trx1) and its wildtype (wt) were subjected to cecal ligation and double puncture or sham operation. After 6, 18 and 24 h, antioxidant enzymes, protein carbonylation and mitocondrial function were evaluated. Hearts were isolated and perfused using the Langendorff technique. Inotropism was evaluated through left ventricular developed pressure (LVDP) and contractile reserve after β-adrenergic stimulus by addition of isoproterenol (ISO) (1 μM). Evaluation of mitochondrial fusion-fission dynamics (Drp1, Mfn2, Opa1) and biogenesis (PGC-1α, NRF-1 and TFAM) were made by real-time qPCR.
Results: Over the time course of sepsis, there was an improvement in average life expectancy in Tg-trx1 (Tg-trx1: 36, wt: 28 h; p=0.0204), and 15 percentages points higher β -adrenergic response at 6 h compared to wt (22.8 vs 7.8%, means of relative percentage differences respectively). Inhibition of complex I activity, protein oxidation, and loss of membrane potential was lower in Tg-trx1, with a sustained MnSOD activity at 24 h. mRNA levels of Opa1 were significantly reduced in sepsis, accompanied by ultrastructural alterations in mitochondrial cristae, while significant Drp1 activation (measured by Ser P616 phosphorylation) was observed in wt mice at 24 h. PGC-1 α mRNA decreased at 6 h in both groups, and then, showed a 2.5-fold increase in Tg-trx1 at 24 h. Autophagy was demonstrated by increased LC3-II/LC3-I ratios in both groups during the progression of sepsis, although the levels were early higher in Tg-Trx1. No indicators of apoptosis were observed.
Conclusions: The results show that mice with cardiac-specific overexpression of Trx1 have higher survival. Trx1 provides protection against oxidative stress, which seems to preserve contractile reserve and keep mitochondrial biogenesis. Associated with mitochondrial autophagy-processes allow mitochondrial renewal and life extension.
Author Disclosures: J.P. Sanchez-Villamil: None. V. D’Annunzio: None. I. Rebagliati: None. P. Finocchietto: None. J. Peralta: None. C. Morales: None. R.J. Gelpi: None. J.J. Poderoso: None. M.C. Carreras: None.
- © 2015 by American Heart Association, Inc.