7.    High-fat diet abolishes the cardioprotective effects of ischemic postconditioning in murine models despite increased thioredoxin-1 levels

Ischemic Postconditioning (IP) reduces infarct size in healthy experimental models. On the other hand, it has been exposed that dyslipidemia could abolish the infarct size reduction conferred by IP caused by reactive oxygen species damage related to ischemia/reperfusion (I/R) injury. Nevertheless, it has not been shown whether
the lack of protection by IP is related to thioredoxin 1 system (Trx1). Therefore, the aim was to evaluate if IP exerts cardioprotective effect on dyslipidemic mice and determine if this lack of reduction of infarct size is related to changes in mitochondrial bioenergetics and Trx1 expression. C57/BL6 males’ mice were used, fed with control diet (CD) or high-fat diet (HFD) during 12 weeks. We measured clinical biochemistry parameters and the hearts were subjected to 30min of I and 120min R (Langendorff) (Group I/R n=7) or an IP protocol (n=7, 30min I, 6 Cycles of R/I 10sec each and 120min R). We assessed ventricular function, infarct size and Trx1 expression (n=6 per group). Also, we measured oxidative stress by H2O2 production and mitochondrial oxygen consumption on state 3 and 4 (n=5 per group). In HFD mice total cholesterol, LDL and HDL increased compared to CD, but
triglycerides did not change. The behavior of ventricular function was similar in all the groups. In CD-IP the infarct size decreased compared to I/R group (I/R:55.2±2.6vsPI:40.2±1.6 p=0.05). However, the cardioprotection was abolished in HFD mice (I/R:67.0±4.0vs. IP:61.0±4.2). In HFD not only H202 production (42%) but also Trx1 expression (2.5-fold) increased; and State 3 mitochondrial oxygen consumption in basal conditions decreased 24% respect to CD. We conclude that in HFD mice there is an alteration of the redox state and the mitochondrial
bioenergetics enough to trigger the endogenous antioxidant response. These changes were accompanied by the lack of protection by IP in HFD mice, even though Trx1 levels has been increased.