Age-dependent cardiac function during experimental sepsis: effect of pharmacological activation of AMP-activated protein kinase by AICAR. Am J Physiol Heart Circ Physiol 2018 Oct 01;315(4):H826-H837
Date
07/07/2018Pubmed ID
29979626Pubmed Central ID
PMC6230907DOI
10.1152/ajpheart.00052.2018Scopus ID
2-s2.0-85053714194 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Age represents a major risk factor for multiple organ failure, including cardiac dysfunction, in patients with sepsis. AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis that controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-γ coactivator-1α and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation contributes to age-dependent cardiac injury in young (2-3 mo) and mature adult (11-13 mo) male mice subjected to sepsis by cecal ligation and puncture and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside affords cardioprotective effects. Plasma proinflammatory cytokines and myokine follistatin were similarly elevated in vehicle-treated young and mature adult mice at 18 h after sepsis. However, despite equivalent troponin I and T levels compared with similarly treated young mice, vehicle-treated mature adult mice exhibited more severe cardiac damage by light and electron microscopy analyses with more marked intercellular edema, inflammatory cell infiltration, and mitochondrial derangement. Echocardiography revealed that vehicle-treated young mice exhibited left ventricular dysfunction after sepsis, whereas mature adult mice exhibited a reduction in stroke volume without apparent changes in load-dependent indexes of cardiac function. At molecular analysis, phosphorylation of the catalytic subunits AMPK-α1/α2 was associated with nuclear translocation of peroxisome proliferator-activated receptor-γ coactivator-1α in vehicle-treated young but not mature adult mice. Treatment with 5-amino-4-imidazole carboxamide riboside ameliorated cardiac architecture derangement in mice of both ages. These cardioprotective effects were associated with attenuation of the systemic inflammatory response and amelioration of cardiac dysfunction in young mice only, not in mature adult animals. NEW & NOTEWORTHY Our data suggest that sepsis-induced cardiac dysfunction manifests with age-dependent characteristics, which are associated with a distinct regulation of AMP-activated protein kinase-dependent metabolic pathways. Consistent with this age-related deterioration, pharmacological activation of AMP-activated protein kinase may afford cardioprotective effects allowing a partial recovery of cardiac function in young but not mature age.
Author List
Inata Y, Piraino G, Hake PW, O'Connor M, Lahni P, Wolfe V, Schulte C, Moore V, James JM, Zingarelli BMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAge Factors
Aminoimidazole Carboxamide
Animals
Cytokines
Disease Models, Animal
Enzyme Activation
Enzyme Activators
Follistatin
Inflammation Mediators
Male
Mice, Inbred C57BL
Myocardium
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phosphorylation
Ribonucleotides
Sepsis
Signal Transduction
Troponin
Ventricular Dysfunction, Left
Ventricular Function, Left