Effects of wortmannin on cardioprotection exerted by ischemic preconditioning in rat hearts subjected to ischemia-reperfusion

Abstract

Ischemic preconditioning (IPC) is one of the most powerful interventions to reduce ischemia-reperfusion injury. The aim of the present study was to investigate the involvement of the phosphatidylinositol-3-kinases (PI3Ks) family in cardioprotection exerted by IPC and the relationship between preservation of mitochondrial morphology and ATP synthesis capacity. In this regard, macroautophagy (autophagy) is considered a dynamic process involved in the replacement of aged or defective organelles under physiological conditions. IPC consisted of four 5-min cycles of ischemia-reperfusion followed by sustained ischemia. Wortmannin (W), a PI3K family inhibitor, was added to the perfusion medium to study the involvement of autophagy in the beneficial effects of IPC. In the present study, LC3-II/I expression was significantly increased in the IPC group when compared with the control group. The hearts subjected to IPC showed greater degradation of p62 than control groups, establishing the existence of an autophagic flow. Electron microscopy showed that IPC preserves the structural integrity of mitochondria after ischemia and at the end of reperfusion. Moreover, hearts subjected to IPC exhibited increased mitochondrial ATP synthesis. The beneficial effects of IPC were abolished by W in all trials of this study, abolishing the differences between the IPC and control groups. These results suggest that IPC could partly reduce injury by ischemia-reperfusion (I/R) by decreasing mitochondrial damage and promoting autophagy. Since W is a nonspecific inhibitor of the PI3Ks family, further research is required to confirm participation of PI3K in the response to IPC.

Late Exercise Preconditioning Promotes Autophagy against Exhaustive Exercise-Induced Myocardial Injury through the Activation of the AMPK-mTOR-ULK1 Pathway

“…In this study, two additional groups of rats, namely the W+LEP group and W+LEP+EE group (LEP and LEP+EE models were treated with wortmannin, respectively) were used. Wortmannin has been reported to reduce the myocardial protective effects of ischemic conditioning by inhibiting autophagy [34]. In this study, the LC3-II levels were significantly decreased in the W+LEP and W+LEP+EE groups, thus suggesting that pretreatment with wortmannin might inhibit LEPand LEP+EE-induced formation of autophagosomes.…”

H2O2 Signaling‐Triggered PI3K Mediates Mitochondrial Protection to Participate in Early Cardioprotection by Exercise Preconditioning

“…The W + EEP + EE group exhibited swelling, which was validated by an increase in the number of COX4/1-labeled mitochondria. Taken together, we demonstrated that the W + EEP + EE group had insufficient mitochondrial clearance compared to EEP + EE, which was possibly associated with wortmannin-induced inhibition of autophagy resulting in increased oxidative injury [ 11 ]. Therefore, EEP-induced cardioprotection does not affect the morphology of mitochondria, and mitophagy plays a role in protecting against EE-induced mitochondrial alterations.…”

“…Acute cardiovascular stresses such as myocardial infarction (MI), ischemic reperfusion (I/R), or prolonged high-intensity exercise are strongly associated with a rapid increase in oxidative stress levels and morphological alterations in the mitochondria [ 5 – 11 ]. Therefore, oxidative stress acts as both inducer and reflector of mitochondrial dysfunction [ 12 ].…”

“…Cellular phosphoinositide 3-kinase- (PI3K-) dependent macroautophagy plays an essential role in mitophagy [ 20 ]. Wortmannin, a PI3K family inhibitor, could effectively suppress cellular autophagy and Akt phosphorylation in the heart [ 11 ]. As such, the PI3K-dependent pathway is also a fundamental regulator that targets mitochondrial permeability transition pore (mPTP) repression by phosphorylating the transmembrane pore protein, voltage-dependent anion channel (VDAC) [ 27 , 28 ].…”

Altered expression levels of autophagy-associated proteins during exercise preconditioning indicate the involvement of autophagy in cardioprotection against exercise-induced myocardial injury

“…In both EP and IP, the autophagy maintenance of ATP synthesis capacity is crucial to generating the adaptive promotion for additional cardiovascular stress. Such effects could be eliminated by PI3K inhibition, which is a possible mechanism to explain the suppression of ischemia-hypoxia in high-intensity exercise [12,37]. However, disruption between the autophagosome and lysosomes may reduce the efficiency of autophagy, resulting in interruption of the autophagic flux [38].…”