α-Lipoic Acid Reduces Infarct Size and Preserves Cardiac Function in Rat Myocardial Ischemia/Reperfusion Injury through Activation of PI3K/Akt/Nrf2 Pathway

<div><p>Background</p><p>The present study investigates the effects and mechanisms of α-Lipoic acid (LA) on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in rat hearts subjected to in vivo myocardial ischemia/reperfusion (MI/R) injury.</p> <p>Methodology/Principal Findings</p><p>Male adult rats underwent 30 minutes of ischemia followed by 3, 24, or 72 h of reperfusion. Animals were pretreated with LA or vehicle before coronary artery ligation. The level of MI/R- induced LDH and CK release, infarct size, cardiomyocyte apoptosis and cardiac functional impairment were examined and compared. Western blot analysis was performed to elucidate the mechanism of LA pretreatment. The level of inflammatory cytokine TNF-α released to serum and accumulated in injured myocardium as well as neutrophil accumulation in injured myocardium were also examined after MI/R injury. Our results reveal that LA administration significantly reduced LDH and CK release, attenuated myocardial infarct size, decreased cardiomyocytes apoptosis, and partially preserved heart function. Western blot analysis showed that LA pretreatment up-regulated Akt phosphorylation and Nrf2 nuclear translocation while producing no impact on p38MAPK activation or nitric oxide (NO) production. LA pretreatment also increased expression of HO-1, a major target of Nrf2. LA treatment inhibited neutrophil accumulation and release of TNF-α. Moreover, PI3K inhibition abolished the beneficial effects of LA.</p> <p>Conclusions/Significance</p><p>This study indicates that LA attenuates cardiac dysfunction by reducing cardiomyoctyes necrosis, apoptosis and inflammation after MI/R. LA exerts its action by activating the PI3K/Akt pathway as well as subsequent Nrf2 nuclear translocation and induction of cytoprotective genes such as HO-1.</p> </div

LA alleviates neutrophil infiltration and TNF-α levels elevation.

<p>LA reduced the MPO activity in I/R compared with vechicle and the wortmannin group (a). LA reduced serum levels of TNF-α compared with the I/R+V group and the wortmannin-pretreated group (b). LA reduced cardiac levels of TNF-α compared with the I/R+V group and the wortmannin-pretreated group (c). The columns and errors bars represent means and SEM. *<i>p</i><0.05 vs sham I/R, ^#<i>p</i><0.05 vs I/R+V, ^ψ<i>P</i><0.05 vs I/R+LA.</p

LA reduces LDH and CK release.

<p>LA reduced CK and LDH level after I/R injury in rat serum. PI3K inhibitor wortmannin cotreatment statistically increased the release of LDH and CK compared with LA treated alone. The columns and errors bars represent means and SEM. *<i>p</i><0.05 vs sham I/R, ^#<i>p</i><0.05 vs I/R+V, ^ψ<i>P</i><0.05 vs I/R+LA.</p