title: Role of TFEB Mediated Autophagy, Oxidative Stress, Inflammation, and Cell Death in Endotoxin Induced Myocardial Toxicity of Young and Aged Mice.
abstract: Elderly patients are susceptible to sepsis. LPS induced myocardial injury is a widely used animal model to assess sepsis induced cardiac dysfunction. The age dependent mechanisms behind sepsis susceptibility were not studied. We analyzed age associated changes to cardiac function, cell death, inflammation, oxidative stress, and autophagy in LPS induced myocardial injury. Both young and aged C57BL/6 mice were used for LPS administration. The results demonstrated that LPS induced more cardiac injury (creatine kinase, lactate dehydrogenase, troponin I, and cardiac myosin-light chains 1), cardiac dysfunction (left ventricular inner dimension, LVID, and ejection fraction (EF)), cell death, inflammation, and oxidative stress in aged mice compared to young mice. However, a significant age dependent decline in autophagy was observed. Translocation of Transcription Factor EB (TFEB) to nucleus and formation of LC3-II were significantly reduced in LPS administered aged mice compared to young ones. In addition to that, downstream effector of TFEB, LAMP-1, was induced in response to LPS challenge in young mice. The present study newly demonstrates that TFEB mediated autophagy is crucial for protection against LPS induced myocardial injury particularly in aging senescent heart. Targeting this autophagy-oxidative stress-inflammation-cell death axis may provide a novel therapeutic strategy for cardioprotection in the elderly.
authors.affiliation: Department of Health, Jinan Central Hospital, Shandong University, Jinan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Jinan Central Hospital, Shandong University, Jinan, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lang
authors.affiliation: Central Laboratory, Jinan Central Hospital, Shandong University, Jinan, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Liangdong
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Enkui
authors.initials: E
authors.lastname: Hao
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D004731:Endotoxins / Q000633:toxicity*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004731:Endotoxins; D008070:Lipopolysaccharides; C484068:Tcfeb protein, mouse