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

ABSTRACT: Previous studies have shown that early exercise preconditioning (EEP) imparts a protective effect on acute cardiovascular stress. However, how mitophagy participates in exercise preconditioning- (EP-) induced cardioprotection remains unclear. EEP may involve mitochondrial protection, which presumably crosstalks with predominant H2O2 oxidative stress. Our EEP protocol involves four periods of 10?min running with 10?min recovery intervals. We added a period of exhaustive running and a pretreatment using phosphoinositide 3-kinase (PI3K)/autophagy inhibitor wortmannin to test this protective effect. By using transmission electron microscopy (TEM), laser scanning confocal microscopy, and other molecular biotechnology methods, we detected related markers and specifically analyzed the relationship between mitophagic proteins and mitochondrial translocation. We determined that exhaustive exercise associated with various elevated injuries targeted the myocardium, oxidative stress, hypoxia-ischemia, and mitochondrial ultrastructure. However, exhaustion induced limited mitochondrial protection through a H2O2-independent manner to inhibit voltage-dependent anion channel isoform 1 (VDAC1) instead of mitophagy. EEP was apparently safe to the heart. In EEP-induced cardioprotection, EEP provided suppression to exhaustive exercise (EE) injuries by translocating Bnip3 to the mitochondria by recruiting the autophagosome protein LC3 to induce mitophagy, which is potentially triggered by H2O2 and influenced by Beclin1-dependent autophagy. Pretreatment with the wortmannin further attenuated these effects induced by EEP and resulted in the expression of proapoptotic phenotypes such as oxidative injury, elevated Beclin1/Bcl-2 ratio, cytochrome c leakage, mitochondrial dynamin-1-like protein (Drp-1) expression, and VDAC1 dephosphorylation. These observations suggest that H2O2 generation regulates mitochondrial protection in EEP-induced cardioprotection.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC6083504 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Yuan Yang Y Pan Shan-Shan SS Wan Dong-Feng DF Lu Jiao J Huang Yue Y

Oxidative medicine and cellular longevity 20180725

Previous studies have shown that early exercise preconditioning (EEP) imparts a protective effect on acute cardiovascular stress. However, how mitophagy participates in exercise preconditioning- (EP-) induced cardioprotection remains unclear. EEP may involve mitochondrial protection, which presumably crosstalks with predominant H2O2 oxidative stress. Our EEP protocol involves four periods of 10 min running with 10 min recovery intervals. We added a period of exhaustive runn ...[more]

PMID: 30147831

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Project description:G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial K+-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 ?M), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results.

Dataset Information

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

Publications

H<sub>2</sub>O<sub>2</sub> Signaling-Triggered PI3K Mediates Mitochondrial Protection to Participate in Early Cardioprotection by Exercise Preconditioning.

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