Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion

Abstract

Ischemia is known to potently stimulate autophagy in the heart, which may contribute to cardiomyocyte survival. In vitro, transfection with small interfering RNAs targeting Atg5 or Lamp-2 (an autophagy-related gene necessary, respectively, for the initiation and digestion step of autophagy), which specifically inhibited autophagy, diminished survival among cultured cardiomyocytes subjected to anoxia and significantly reduced their ATP content, confirming an autophagy-mediated protective effect against anoxia. We next examined the dynamics of cardiomyocyte autophagy and the effects of manipulating autophagy during acute myocardial infarction in vivo. Myocardial infarction was induced by permanent ligation of the left coronary artery in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice in which GFP-LC3 aggregates to be visible in the cytoplasm when autophagy is activated. Autophagy was rapidly (within 30 min after coronary ligation) activated in cardiomyocytes, and autophagic activity was particularly strong in salvaged cardiomyocytes bordering the infarcted area. Treatment with bafilomycin A1, an autophagy inhibitor, significantly increased infarct size (31% expansion) 24 h postinfarction. Interestingly, acute infarct size was significantly reduced (23% reduction) in starved mice showing prominent autophagy before infarction. Treatment with bafilomycin A1 reduced postinfarction myocardial ATP content, whereas starvation increased myocardial levels of amino acids and ATP, and the combined effects of bafilomycin A1 and starvation on acute infarct size offset one another. The present findings suggest that autophagy is an innate and potent process that protects cardiomyocytes from ischemic death during acute myocardial infarction.

p27 Protein Protects Metabolically Stressed Cardiomyocytes from Apoptosis by Promoting Autophagy

“…Having said this, it remains controversial whether activation of autophagy is beneficial or detrimental in load-induced remodeling (7,32), whereas augmenting autophagy has been more consistent in protecting against postischemic remodeling (33)(34)(35). Nakai et al demonstrated that the cardiac-specific knock-out of ATG5 in adult mice led to cardiac hypertrophy, LV dilatation, and contractile dysfunction (7).…”

“…These conflicting reports regarding the protective versus maladaptive effects of specific autophagy regulators stand in contrast to data from mouse and rat LAD occlusion model of MI. In this model, Kanamori et al found in mouse that levels of autophagy were greatest in the infarct border zone during the first week post-MI, then greatest in remote areas of the heart during the chronic stage (3 weeks post-MI) and that blocking autophagy (with Baf-A1) exacerbated cardiac dysfunction, although enhancing autophagy (with rapamycin) reduced cardiac dysfunction and remodeling (33,34). Consistent with this, Buss et al reported in rat that the mTOR inhibitor everolimus also increased autophagy and prevented adverse cardiac remodeling post-MI (35).…”

Cellular Pathways of Death and Survival in Acute Myocardial Infarction

“…During these processes, CMs are able to elicit the cardioprotective process of autophagy to alter the fate of struggling CMs in order to survive the hypoxic cellular conditions and prevent cell death. The interaction between each of these cellular processes with common signaling mediators (Figure 2) will determine the fate of ischemic CMs with the balance that occurs in the peri-infarct area most likely playing a vital role in CM preservation of functional capacity via appropriate autophagic flux and mitigation of apoptosis and inflammation [27,65,92]. With an in-depth understanding of the factors that determine the balance between cellular survival and death of CMs in response to acute MI, novel therapeutics can be developed to promote CM survival during the initial ischemic insult and improve cardiac function following MI.…”

“…In a permanent coronary artery occlusion model, autophagy was shown to be activated within 30 minutes of ischemia and noted to be strongly activated in the peri-infarct area [65]. Inhibition of mTOR with everolimus resulted in increased LC3 expression in the border zone of infarction, also suggesting autophagic activity is more prominent in the peri-infarct CMs (Figure 2) [66].…”

Sevoflurane induces cardioprotection through reactive oxygen species-mediated upregulation of autophagy in isolated guinea pig hearts

“…This is an evolutionally conserved process crucial for normal tissue homeostasis. Accumulating evidence suggests that autophagy is stimulated by ischemia and actually contributes to cardiomyocyte survival [26,27]. A recent study has shown that autophagy induced by ischemic preconditioning is essential for cardioprotection [28].…”