Autophagy Induced by Ischemic Preconditioning is Essential for Cardioprotection

Abstract

Based on growing evidence linking autophagy to preconditioning, we tested the hypothesis that autophagy is necessary for cardioprotection conferred by ischemic preconditioning (IPC). We induced IPC with three cycles of 5 min regional ischemia alternating with 5 min reperfusion and assessed the induction of autophagy in mCherry-LC3 transgenic mice by imaging of fluorescent autophagosomes in cryosections. We found a rapid and significant increase in the number of autophagosomes in the risk zone of the preconditioned hearts. In Langendorff-perfused hearts subjected to an IPC protocol of 3×5 min ischemia, we also observed an increase in autophagy within 10 min, as assessed by Western blotting for p62 and cadaverine dye binding. To establish the role of autophagy in IPC cardioprotection, we inhibited autophagy with Tat-ATG5 K130R , a dominant negative mutation of the autophagy protein Atg5. Cardioprotection by IPC was reduced in rat hearts perfused with recombinant Tat-ATG5 K130R . To extend the potential significance of autophagy in cardioprotection, we also assessed three structurally unrelated cardioprotective agents-UTP, diazoxide, and ranolazine-for their ability to induce autophagy in HL-1 cells. We found that all three agents induced autophagy; inhibition of autophagy abolished their protective effect. Taken together, these findings establish autophagy as an end-effector in ischemic and pharmacologic preconditioning.

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

“…This suggests that the preconditioning effect of the lysosomal degradative pathways on maintenance of mitochondrial quality (as demonstrated by our data in Figs. 2G and 4G), 19 and perhaps on maintenance of ER homeostasis 63 plays a central role in shoring up cellular defenses to withstand the stress. 64 Indeed, we observe a reduction in prevalence of depolarized mitochondria in repetitively starved cardiomyocytes, in vitro (Fig.…”

“…Activation of autophagy is also essential for cytoprotection during myocardial ischemia, 17 and pharmacologic stimulation of autophagy with rapamycin protects against postinfarction remodeling. 18 Myocardial autophagy is also induced with regimens of ischemic preconditioning; 19,20 and appears essential for the observed ischemic cytoprotection in ex-vivo ischemia-reperfusion injury. 19 Whether calorie restriction-induced autophagy confers ischemic cardioprotection is not known.…”

“…18 Myocardial autophagy is also induced with regimens of ischemic preconditioning; 19,20 and appears essential for the observed ischemic cytoprotection in ex-vivo ischemia-reperfusion injury. 19 Whether calorie restriction-induced autophagy confers ischemic cardioprotection is not known.…”

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats

“…Ischemic preconditioning also induces autophagy to promote cardioprotective effects [15,16] . Housekeeping levels of autophagy are required for normal cardiac action; however, the autophagy response to stimuli is either an adaptive response or a detrimental effect [9] .…”

The endoplasmic reticulum stress inhibitor salubrinal inhibits the activation of autophagy and neuroprotection induced by brain ischemic preconditioning

“…Autophagy is known to be activated during ischemic insult, but its contribution to neuronal death/survival is still being debated [16][17][18] . Recent reports also suggested an association between preconditioning and autophagy in both the heart and brain [19][20][21][22] . In an earlier study, we demonstrated that the neuroprotection induced by IPC is mediated by autophagy in a rat model of IPC, and the pharmacological induction of autophagy mimics the neuroprotection of IPC [23] .…”