Remote Ischemic Preconditioning Induces Cardioprotective Autophagy and Signals through the IL-6-Dependent JAK-STAT Pathway

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.

Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning

“…4 and 7 ). These findings are consistent with our previous reports showing that RIC increases autophagy signaling in several different models [ 25 , 26 , 47 – 49 ]. However, in some reports, albeit in different models with different RIC protocols (in large animals subjected to intracoronary doxorubicin infusion [ 31 ], an acute human cardiac surgical intraoperative study [ 32 ] and doxorubicin toxicity in a mouse model [ 33 ]) have shown that RIC has no effect or even decreases autophagy signaling, emphasizing the need for disease-specific models in regard to the effects of RIC.…”

Exploring the role of neurogenic pathway-linked cholecystokinin release in remote preconditioning-induced cardioprotection

“…The isolated hearts were mounted on the Langendorff system and perfused with perfused with Kreb's Henseleit solution at 37°C. The inflow of physiological solution was stopped for 30 minutes to induce global ischemia and afterwards, the flow of KH was reinstituted for 120 minutes to establish reperfusion 18 , 19 .…”

The NRF2 stimulating agent, tin protoporphyrin, activates protective cytokine pathways in healthy human subjects and in patients with chronic kidney disease

“…This suggests that resident splenic (and possibly circulating) T cells and B cells were the sources of the SnPP-triggered the five-to sevenfold plasma IL-10 increases. Although IL-6 has long been considered to be a pro-inflammatory cytokine, it also exerts potent anti-inflammatory effects (Billah et al, 2019(Billah et al, , 2020Filho et al, 2015;Kimizuka et al, 2004;McGinnis et al, 2015;Nechemia-Arbely et al, 2008). As examples, IL-6 can suppress production of pro-inflammatory cytokines and their receptors.…”