Loss of myocardial protection against myocardial infarction in middle-aged transgenic mice overexpressing cardiac thioredoxin-1.

PEREZ V; D' ANNUNZIO V; LLAMOSAS C; GOMÉZ A; WULF N; CICALE E; CASANOVA V; GELPI RJ

Melbourne

Congreso; world heart congress of 2014; 2014

World Heart Federation

Introduction Thioredoxin-1 (Trx1) protects the heart from ischemia/reperfusion (I/R) injury but this protection is abolished in elderly mice. However, it's not clear whether this also occurs in middle-age, when the deleterious effects of aging are already taking place. This absence of studies in middle-aged patients is striking, since it's known that ischemic episodes in patients start manifesting themselves during middle-age and they are not exclusive of advanced age.     Objectives The present study was designed to determine whether Trx1 expression and activity, as well as p-Akt, are altered in young and middle-aged (MA) transgenic mice overexpressing cardiac Trx1, in a way that may contribute to increased susceptibility to myocardial I/R.   Methods Langendorff-perfused hearts were subjected to 30 minutes of global ischemia followed by 120 minutes of reperfusion. We used 3 and 12 month-old male wild type (WT) mice (WT-Y, n=8 and WT-MA, n=7 respectively) and 3 and 12 month-old mice overexpressing cardiac Trx1 (Trx1-Y, n=7 and Trx1-MA, n=6 respectively). Infarct size (TTC) was measured. Trx1, Akt and p-Akt (Ser473) expression (western blot), Trx1 activity (insulin reduction assay), and nitration (western blot) were also measured.   Results Infarct size was 46.8±4.1% in WT-Y, 52.6±5.2% in WT-MA, 27.3±3.5% in Trx1-Y (p<0.05), and 49.1±6.3% in Trx1-MA. Although Trx1 expression in Trx1-Y and Trx1-MA was the same, Trx1 activity was significantly reduced by 57.0±5.2% (P< 0.05) in Trx1-MA. The reduction in activity in Trx1-MA was accompanied by an increase in nitration by 17.5±0.9% (p<0.05). The expression of p-Akt showed a significant increase during reperfusion, with respect to the pre-ischemic values in Trx1-Y (1.55±0.05 AU vs. 0.96±0.06 AU, p< 0.05), while it did not increase during reperfusion in Trx1-MA (0.90±0.08 AU vs. 0.87±0.10 AU).   Conclusion As expected, Trx1 cardiac overexpression reduced infarct size in young but not in middle-aged mice. The lack of protection in transgenic middle-aged mice even with normal Trx1 expression may be associated to decreased Trx1 activity, increased nitration and inhibition of p-Akt (Ser473).