title: Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling.
abstract: Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5-aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS-null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Michaella M
authors.initials: MM
authors.lastname: Reif
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Craige
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: shashi.kant@umassmed.edu.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kant
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: john.keaney@umassmed.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000222:Adaptation, Physiological; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D020536:Enzyme Activators; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000001:Calcimycin; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D000076222:Mechanistic Target of Rapamycin Complex 1; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus
keywords: AICAR; AMPK; Endothelial dysfunction; Mitochondrial biogenesis; Nitric oxide; Rapamycin; eNOS; mTORC1