Abstract
Autophagy is a cellular process by which mammalian cells degrade and assist in recycling damaged organelles and proteins. This study aimed to ascertain the role of autophagy in remote ischemic preconditioning (RIPC)-induced cardioprotection. Sprague Dawley rats were subjected to RIPC at the hindlimb followed by a 30-min transient blockade of the left coronary artery to simulate ischemia reperfusion (I/R) injury. Hindlimb muscle and the heart were excised 24 h post reperfusion. RIPC prior to I/R upregulated autophagy in the rat heart at 24 h post reperfusion. In vitro, autophagy inhibition or stimulation prior to RIPC, respectively, either ameliorated or stimulated the cardioprotective effect, measured as improved cell viability to mimic the preconditioning effect. Recombinant interleukin-6 (IL-6) treatment prior to I/R increased in vitro autophagy in a dose-dependent manner, activating the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway without affecting the other kinase pathways, such as p38 mitogen-activated protein kinases (MAPK), and glycogen synthase kinase 3 Beta (GSK-3β) pathways. Prior to I/R, in vitro inhibition of the JAK-STAT pathway reduced autophagy upregulation despite recombinant IL-6 pre-treatment. Autophagy is an essential component of RIPC-induced cardioprotection that may upregulate autophagy through an IL-6/JAK-STAT-dependent mechanism, thus identifying a potentially new therapeutic option for the treatment of ischemic heart disease.
Highlights
Myocardial infarction (MI) is one of the leading causes of mortality and morbidity worldwide
We previously demonstrated in a rat model of remote ischemic preconditioning (RIPC) that hind limb preconditioning can protect the heart from ischemia reperfusion (I/R) injury by upregulating the JAK-signal transducer and activator of transcription (STAT) signaling mechanism [32]
LC3-II was significantly increased in remote hypoxic preconditioning (RHPC) H/R compared to the H/R group (1.95 ± 0.21 vs. 1.38 ± 0.11-fold relative to normoxic control, p < 0.05) (Figure 1B)
Summary
Myocardial infarction (MI) is one of the leading causes of mortality and morbidity worldwide. Brief episodes of non-lethal ischemia to the heart prior to MI can reduce MI damage [1] This endogenous cardioprotective phenomenon cannot be applied to MI patients, as they present with a blocked coronary artery. As an adjunct therapy to standard patient care, RIPC has been demonstrated to reduce cardiac mortality and hospitalization for heart failure patients [14], and improves the myocardial salvage index [15] in ST-elevation myocardial infarction (STEMI) patients. A large multi-center trial with cardiac death and hospitalization for heart failure at one year as clinical endpoints in STEMI patients treated with PCI could not deliver any clinical benefit with RIPC [16]. We have previously summarized the effect of RIPC on PCI and coronary artery bypass grafting (CABG) patients [13]
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