Post-TTM Rebound Pyrexia after Ischemia-Reperfusion Injury Results in Sterile Inflammation and Apoptosis in Cardiomyocytes

Abstract

Introduction Fever is frequently observed after acute ischemic events and is associated with poor outcome and higher mortality. Targeted temperature management (TTM) is recommended for neuroprotection in comatose cardiac arrest survivors, but pyrexia after rewarming is proven to be detrimental in clinical trials. However, the cellular mechanisms and kinetics of post-TTM rebound pyrexia remain to be elucidated. Therefore, we investigated the effects of cooling and post-TTM pyrexia on the inflammatory response and apoptosis in a cardiomyocyte ischemia-reperfusion (IR) injury model. Methods HL-1 cardiomyocytes were divided into the following groups to investigate the effect of oxygen-glucose deprivation/reperfusion (OGD/R), hypothermia (33.5°C), and pyrexia (40°C): normoxia controls maintained at 37°C and warmed to 40°C, OGD/R groups maintained at 37°C and cooled to 33.5°C for 24 h with rewarming to 37°C, and OGD/R pyrexia groups further warmed from 37 to 40°C. Caspase-3 and RBM3 were assessed by Western blot and TNF-α, IL-6, IL-1β, SOCS3, iNOS, and RBM3 transcriptions by RT-qPCR. Results OGD-induced oxidative stress (iNOS) in cardiomyocytes was attenuated post-TTM by cooling. Cytokine transcriptions were suppressed by OGD, while reperfusion induced significant TNF-α transcription that was exacerbated by cooling. Significant inductions of TNF-α, IL-6, IL-1β, and SOCS3 were observed in noncooled, but not in cooled and rewarmed, OGD/R-injured cardiomyocytes. Further warming to pyrexia induced a sterile inflammatory response in OGD/R-injured groups that was attenuated by previous cooling, but no inflammation was observed in pyrexic normoxia groups. Moreover, cytoprotective RBM3 expression was induced by cooling but suppressed by pyrexia, correlating with apoptotic caspase-3 activation. Conclusion Our findings show that maintaining a period of post-TTM “therapeutic normothermia” is effective in preventing secondary apoptosis-driven myocardial cell death, thus minimizing the infarct area and further release of mediators of the innate sterile inflammatory response after acute IR injury.

Oxymatrine pretreatment protects H9c2 cardiomyocytes from hypoxia/reoxygenation injury by modulating the PI3K/Akt pathway

“…In some patients with CAD, the rupture of atherosclerotic plaques in the coronary arteries due to fatigue, stress and other factors leads to the rapid accumulation of platelets, neutrophils and macrophages, which form emboli and block the vascular cavity, leading to the necrosis of cardiomyocytes. Myocardial cells are non-renewable, and thus myocardial blood perfusion must be restored as soon as possible ( 20 ). However, although the continuous development of PCI, CABG and other technologies has effectively improved myocardial blood perfusion, I/R injury is a major problem that remains to be addressed.…”

Clinical Effect of Post-rewarming Fever after Targeted Temperature Management in Cardiac Arrest Patients: A Systematic Review and Meta-Analysis

“…[34] And in an in vitro study, the prevention of PRF obviously aggravated apoptosis of cells and release of in ammatory factors. [35] This study suggested that PRF was related to activation of in ammatory response and programmed cell death following the ischemia-reperfusion injury caused by CA. Since most works are focused on the clinical application of TTM, including optimal cooling temperature [5,36,37], practical methods of cooling for temperature control[6, 38, 39] and rate of rewarming following TTM [40,41], it is necessary to investigate the PRF with different body temperature and body temperature control in the future.…”

ThermomiR-377-3p-induced Suppression of Cirbp Expression Is Required for Effective Elimination of Cancer Cells and Cancer Stem-like Cells by Hyperthermia

“…The previous study indicated that Rbm3 expression was reduced during fever/pyrexia, and reduced Rbm3 expression in turn led to elevated expression of Rbm3-targeted temperature-sensitive miRNAs (termed thermomiRs), such as miR-142-5p and miR-143 [83]. Moreover, cytoprotective Rbm3 expression was induced by cooling but suppressed by pyrexia in cardiomyocytes [84]. Together, these aforementioned ndings strongly suggests that Cirbp and Rbm3 might be implicated in hyperthermia for cancer therapy.…”