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Role of the mTOR Signalling Pathway in Human Sepsis-Induced Myocardial Dysfunction

Published on Apr 1, 2019in Canadian Journal of Cardiology 5.59
· DOI :10.1016/j.cjca.2019.03.022
Wei Cheng1
Estimated H-index: 1
(Peking Union Medical College Hospital),
Wei Cheng Mm (Peking Union Medical College Hospital)+ 3 AuthorsNa Cui5
Estimated H-index: 5
(Peking Union Medical College Hospital)
Abstract Background Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication of sepsis. Mammalian target of rapamycin (mTOR) signalling pathway is significantly associated with SIMD in an animal model; however, there have been no clinical studies of the association in humans. Methods We enrolled 88 patients with sepsis who were admitted to the intensive care unit (ICU) between April 2017, and April 2018. Biochemical indexes, hemodynamic parameters, and bedside echocardiographic parameters were recorded. Serum levels of mTOR, phosphorylated ribosome S6 protein kinase (PS6K), microtubule-associated protein light chain 3 type II (LC3B), Bcl-2-interacting mediator of cell death (BIM), interleukin 6, interleukin 10, and interferon-γ were examined. Results Compared with non-SIMD patients, patients with SIMD had higher ICU and 28-day mortality, PS6K and BIM levels, but lower LC3B levels. Serum PS6K levels in patients with SIMD were significantly negatively and positively correlated with LC3B and BIM, respectively. Multivariate regression analysis revealed that PS6K concentration at admission was an independent predictor of 28-day mortality. Receiver operating characteristic curve analysis indicated that a PS6K concentration cutoff of 42.43 pg/mL at ICU admission could predict the incidence of SIMD with a sensitivity and specificity of 91.7% and 96.2%, whereas a cutoff concentration of 41.17 pg/mL PS6K could predict 28-day mortality with a sensitivity and specificity of 83.3% and 54.3%, respectively. Conclusions Patients with sepsis and SIMD had higher ICU and 28-day mortality. Higher serum PS6K concentrations were significantly associated with SIMD incidence and 28-day mortality, suggesting that activation of the mTOR pathway may play a major role in SIMD.
  • References (22)
  • Citations (1)
Published on Jun 28, 2018in Mediators of Inflammation 3.54
Wen Han2
Estimated H-index: 2
(Peking Union Medical College Hospital),
Hao Wang6
Estimated H-index: 6
(Peking Union Medical College Hospital)
+ 3 AuthorsDawei Liu11
Estimated H-index: 11
(Peking Union Medical College Hospital)
Background. Sepsis-induced myocardial dysfunction is a severe clinical problem. Recent studies have indicated that autophagy and myocardial energy depletion play a major role in myocardial dysfunction during sepsis, a mechanistic target of rapamycin (mTOR) as a master sensor of energy status and autophagy mediator; however, there are little data describing its role during sepsis in the heart. Methods. Cecal ligation and puncture (CLP) or sham operation (SHAM) was performed in rats. After treatme...
Published on Jan 1, 2018in Critical Care Medicine 6.97
Gina Cassel1
Estimated H-index: 1
Jules Beal1
Estimated H-index: 1
+ 3 AuthorsChhavi Katyal5
Estimated H-index: 5
Published on Oct 1, 2017in Biochemical and Biophysical Research Communications 2.71
Jie Zhang1
Estimated H-index: 1
(UMMC: University of Mississippi Medical Center),
Peng Zhao1
Estimated H-index: 1
(SDU: Shandong University)
+ 5 AuthorsJi Li6
Estimated H-index: 6
(UMMC: University of Mississippi Medical Center)
Abstract AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the...
Published on Jan 1, 2017in Oxidative Medicine and Cellular Longevity 4.87
Dajun Zhao2
Estimated H-index: 2
Jian Yang14
Estimated H-index: 14
Lifang Yang4
Estimated H-index: 4
Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (...
Published on Jun 1, 2016in Cell Metabolism 22.41
Brian K. Kennedy64
Estimated H-index: 64
(Buck Institute for Research on Aging),
Dudley W. Lamming32
Estimated H-index: 32
(UW: University of Wisconsin-Madison)
Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal ...
Published on Feb 23, 2016in JAMA 51.27
Mervyn Singer68
Estimated H-index: 68
(UCL: University College London),
Clifford S. Deutschman34
Estimated H-index: 34
(The Feinstein Institute for Medical Research)
+ 16 AuthorsCraig M. Coopersmith16
Estimated H-index: 16
(Emory University)
Importance Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. Objective To evaluate and, as needed, update definitions for sepsis and septic shock. Process A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epide...
Published on Dec 1, 2015in Journal of intensive care
Ryota Sato3
Estimated H-index: 3
Michitaka Nasu3
Estimated H-index: 3
Sepsis-induced cardiomyopathy is a reversible myocardial dysfunction that typically resolves in 7–10 days. It is characterized by left ventricular dilatation and depressed ejection fraction. However, many uncertainties exist regarding the mechanisms, characteristics, and treatments of this condition. Therefore, this review attempts to summarize our current knowledge of sepsis-induced cardiomyopathy.
Published on Dec 1, 2014in Journal of Geriatric Cardiology 1.76
Carol Chen-Scarabelli15
Estimated H-index: 15
Pratik R. Agrawal4
Estimated H-index: 4
+ 7 AuthorsRichard A. Knight47
Estimated H-index: 47
A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cytoplasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion (I/R) injury. This tightly orchestrated catabolic cellular ‘housekeeping’ process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can ...
Published on Mar 1, 2014in Shock 3.08
Chih-Wen Lin6
Estimated H-index: 6
Steven Lo7
Estimated H-index: 7
+ 7 AuthorsYa-Ching Hsieh5
Estimated H-index: 5