Role of TFEB Mediated Autophagy, Oxidative Stress, Inflammation, and Cell Death in Endotoxin Induced Myocardial Toxicity of Young and Aged Mice

• Published in: Oxidative medicine and cellular longevity 2016-01, Vol.2016 (2016), p.1-10
• Main Authors: Wang, Yidan, Xu, Liangdong, Zhang, Huilin, Lang, Fangfang, Li, Fang, Hao, Enkui
• Format: Article
• Language: English
• Subjects: Aging; Aging - metabolism; Aging - pathology; Analysis; Animals; Apoptosis; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biochemistry; Biosynthesis; Cardiomyocytes; Cardiomyopathy; Cell death; Creatine kinase; Diseases; Endotoxins - toxicity; Gene expression; Heart; Heart failure; Homeostasis; Inflammation; Inflammation - metabolism; Inflammation - pathology; Laboratories; Lipopolysaccharides; Male; Membranes; Mice, Inbred C57BL; Mitochondria; Myocardium - metabolism; Myocardium - pathology; Myosin; Older people; Oxidative Stress; Proteins; Rodents; Sepsis; Signal Transduction - drug effects; Statistical analysis
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2016/5380319

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.