title: The AMPK Activator Aicar Ameliorates Age-Dependent Myocardial Injury in Murine Hemorrhagic Shock.
abstract: The development of myocardial dysfunction in patients with hemorrhagic shock is significantly impacted by the patient age. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of energy homeostasis, which coordinates metabolic recovery after cellular stress. We investigated whether AMPK-regulated pathways are age-dependent in hemorrhage-induced myocardial injury and whether AMPK activation by 5-amino-4-imidazolecarboxamide riboside (AICAR) affords cardioprotective effects. Anesthetized C57/BL6 young (3-5 months old) and mature (9-12 months old) male mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with shed blood and Lactated Ringer's solution. Mice were sacrificed at 3 h after resuscitation, and plasma and hearts were harvested for biochemical assays. Vehicle-treated mature mice exhibited higher myocardial injury and higher levels of plasma biomarkers of cardiovascular injury (endocan and follistatin) when compared with young mice. Cardiac cell mitochondrial structure was also markedly impaired in vehicle-treated mature mice when compared with young mice. At molecular analysis, an increase of the phosphorylated catalytic subunit pAMPKα was associated with nuclear translocation of the peroxisome proliferator-activated receptor γ coactivator-α in young, but not mature mice. No changes in autophagy were observed as evaluated by the conversion of the light-chain (LC)3B-I protein to LC3B-II form. Treatment with AICAR ameliorated myocardial damage in both age groups. However, AICAR therapeutic effects were less effective in mature mice than young mice and involved distinct mechanisms of action. Thus, our data demonstrate that during hemorrhagic shock AMPK-dependent metabolic mechanisms are important for mitigating myocardial injury. However, these mechanisms are less competent with age.
authors: *Department of Pediatrics, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio†Department of Surgery, University of Cincinnati, Cincinnati, Ohio.
authors: Dzmitry
authors: D
authors: Matsiukevich
authors: Giovanna
authors: G
authors: Piraino
authors: Lindsey R
authors: LR
authors: Klingbeil
authors: Paul W
authors: PW
authors: Hake
authors: Vivian
authors: V
authors: Wolfe
authors: Michael
authors: M
authors: O'Connor
authors: Basilia
authors: B
authors: Zingarelli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000367:Age Factors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D012265:Ribonucleotides / Q000627:therapeutic use*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide