Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rat
- PDF / 2,638,955 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 19 Downloads / 175 Views
ORIGINAL ARTICLE
Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rats After Ischemic Stroke Zhifeng Qi & Wen Dong & Wenjuan Shi & Rongliang Wang & Chencheng Zhang & Yongmei Zhao & Xunming Ji & Ke Jian Liu & Yumin Luo
Received: 13 October 2014 / Revised: 20 January 2015 / Accepted: 16 February 2015 # Springer Science+Business Media New York 2015
Abstract Autophagy, an important intracellular degradation pathway, has been reported to clear impaired mitochondria and reduce mitochondria-mediated injury in ischemic disease. Our study and other recent investigations have shown that AKT-dependent autophagy contributes to the neuroprotection afforded by limb remote ischemic conditioning (RIC) in experimental stroke. However, how AKT triggers RIC-based autophagy and whether RIC-afforded autophagy is beneficial for mitochondrial function after cerebral ischemia remains unclear. The disruption of the Bcl-2/Beclin1 complex has been reported to trigger autophagy formation in the condition of Bcl-2 phosphorylation at Ser70. We investigated whether Bcl-2 phosphorylation triggers RIC-based autophagy and thereby confers RIC-induced neuroprotection against mitochondrial injury, using a transient cerebral ischemic rat model. We demonstrated that rats undergoing RIC treatment 30 min after the onset of ischemia (I-30) and at reperfusion (R-0) significantly upregulated Bcl-2 phosphorylation. Immunoprecipitation revealed that RIC increased dissociation Z. Qi : W. Dong : W. Shi : R. Wang : C. Zhang : Y. Zhao : X. Ji : K. J. Liu : Y. Luo (*) Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China e-mail: [email protected] Z. Qi : W. Dong : W. Shi : R. Wang : C. Zhang : Y. Zhao : X. Ji : Y. Luo Key Laboratory of Neurodegenerative Diseases (Capital Medical University), Ministry of Education, 45 Changchun Street, Beijing 100053, China K. J. Liu (*) Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-0001, USA e-mail: [email protected]
of the Bcl-2/Beclin1 complex, leading to a higher level of autophagy than in ischemia/reperfusion rats. Furthermore, AKT activation was shown to play a critical role in regulating Bcl-2-mediated autophagy, as an AKT inhibitor (LY294002, AKTi) administered 30 min prior to ischemia significantly suppressed Bcl-2 phosphorylation and Bcl-2/Beclin1 complex dissociation, thereby reducing autophagy in RIC rats. Blocking Bcl-2 phosphorylation-dependent autophagy with AKTi suppressed RIC-afforded protection on mitochondrial potential and mitochondrial-dependent cell death effector pathway. These findings indicate that Bcl-2 phosphorylation and thereby Bcl-2/Beclin1 complex disruption play a crucial role in triggering autophagy and reducing mitochondrial damage in RIC rats after cerebral ischemia and require the involvement of the AKT activation. Keywords Conditioning . Autophagy . Cerebral ischemia . Bcl-2 . Mito
Data Loading...
