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2017 ; 8
(2
): e2577
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Berbamine postconditioning protects the heart from ischemia/reperfusion injury
through modulation of autophagy
#MMPMID28151484
Zheng Y
; Gu S
; Li X
; Tan J
; Liu S
; Jiang Y
; Zhang C
; Gao L
; Yang HT
Cell Death Dis
2017[Feb]; 8
(2
): e2577
PMID28151484
show ga
Pretreatment of berbamine protects the heart from ischemia/reperfusion (I/R)
injury. However it is unknown whether it has cardioprotection when given at the
onset of reperfusion (postconditioning (PoC)), a protocol with more clinical
impact. Autophagy is upregulated in I/R myocardium and exacerbates cardiomyocyte
death during reperfusion. However, it is unknown whether the autophagy during
reperfusion is regulated by berbamine. Here we investigated whether berbamine PoC
(BMPoC) protects the heart through regulation of autophagy by analyzing the
effects of BMPoC on infarct size and/or cell death, functional recovery and
autophagy in perfused rat hearts and isolated cardiomyocytes subjected to I/R.
Berbamine from 10 to 100?nM given during the first 5?min of reperfusion
concentration-dependently improved post-ischemic myocardial function and
attenuated cell death. Similar protections were observed in cardiomyocytes
subjected to simulated I/R. Meanwhile, BMPoC prevented I/R-induced impairment of
autophagosome processing in cardiomyocytes, characterized by increased LC3-II
level and GFP-LC3 puncta, and decreased p62 degradation. Besides, lysosomal
inhibitor chloroquine did not induce additional increase of LC3-II and P62
abundance after I/R but it reversed the effects of BMPoC in those parameters in
cardiomyocytes, suggesting that I/R-impaired autophagic flux is restored by
BMPoC. Moreover, I/R injury was accompanied by enhanced expression of Beclin 1,
which was significantly inhibited by BMPoC. In vitro and in vivo
adenovirus-mediated knockdown of Beclin 1 in myocardium and cardiomyocytes
restored I/R-impaired autophagosome processing, associated with an improvement of
post-ischemic recovery of myocardial contractile function and a reduction of cell
death, but it did not have additive effects to BMPoC. Conversely, overexpression
of Beclin 1 abolished the cardioprotection of BMPoC as did by overexpression of
an essential autophagy gene Atg5. Furthermore, BMPoC-mediated cardioprotection
was abolished by a specific Akt1/2 inhibitor A6730. Our results demonstrate that
BMPoC confers cardioprotection by modulating autophagy during reperfusion through
the activation of PI3K/Akt signaling pathway.
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