Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy

Abstract

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.

Knockdown of lncRNA AK139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy

“…For instance, Zheng et al investigated berbamine pre‐treatment on protecting I/R injury in hearts on the basis of autophagy mechanism 19. Ma et al emphasized ALDH2 as therapeutic target for MIRI and it prompting autophagy during ischaemia and remained elevated autophagy at reperfusion 20.…”

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

“…In contrast, excessive autophagy is responsible for self-destruction and ultimately causes autophagic cell death, accompanied by the upregulation of microtubule-associated protein 1 light chain 3 (LC3) and beclin-1 [6]. It has been revealed that dysregulated autophagy is closely related to various cardiac diseases such as myocardial infarction [7], myocardial IR injury [8], and cardiac hypertrophy [9]. A variety of studies have suggested that myocardial ischemia induces autophagy through an AMP-induced protein kinase (AMPK)-dependent mechanism.…”

Molecular mechanisms of autophagy in cardiac ischemia/reperfusion injury (Review)

“…The treatment of rats with wortmannin, an inhibitor of class III PI-3K, has been used to suppress autophagy in many studies (70,71), and attenuates both the LC3-II and BAG-1 protein expressions (67). Zheng et al (72) reported that the activated PI3K/Akt pathway contributes to the berbamine postconditioning-induced cardioprotection through modulating autophagy. The Beclin-1/class III PI-3K pathway-regulated autophagy and autophagy-mediated function in I/R injury are shown in Fig.…”