title: Permissive role of AMPK and autophagy in adiponectin deficiency-accentuated myocardial injury and inflammation in endotoxemia.
abstract: Adiponectin (APN), an adipose-derived adipokine, alleviates lipopolysaccharide (LPS)-induced injury in multiple organs including hearts although the underlying mechanism in endotoxemia remains elusive. This study was designed to examine the role of adiponectin in LPS-induced cardiac anomalies and inflammation as well as the underlying mechanism with a focus on autophagy - a conserved machinery for bulk degradation of intracellular components.
  
  
  
  Wild-type (WT) and APN(-/-) mice were challenged with LPS (4mg/kg) or saline for 6h. Echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated. Markers of autophagy, apoptosis and inflammation including LC3B, p62, Beclin1, AMPK, mTOR, ULK, Caspase 3, Bcl-2, Bax, TLR4, TRAF6, MyD88, IL-1B, TNFα, HMGB1, JNK and IκB were examined using Western blot or RT-PCR. Our results showed that LPS challenge reduced fractional shortening, compromised cardiomyocyte contractile capacity, intracellular Ca(2+) handling properties, apoptosis and inflammation, which were accentuated by adiponectin ablation. Adiponectin ablation unmasked the LPS-induced cardiac remodeling (left ventricular end systolic diameter) and prolongation of cell shortening. The detrimental effects of adiponectin ablation were associated with dampened autophagy in response to LPS through an AMPK-mTOR-ULK1-dependent mechanism. In vivo administration of AMPK activator AICAR or the autophagy inducer rapamycin effectively attenuated or obliterated LPS-induced and adiponectin deficiency-accentuated responses without affecting TLR4, TRAF6 and MyD88.
  
  
  
  The findings suggest that AMPK and autophagy may play a permissive role in the adiponectin deficiency-exacerbated cardiac dysfunction, apoptosis and inflammation under LPS challenge possibly at the post-TLR4 receptor level.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address: ren.jun@zs-hospital.sh.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Sidney Y
authors.initials: SY
authors.lastname: Ren
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Burn and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Maolong
authors.initials: M
authors.lastname: Dong
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address: zhangym197951@126.com.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000172:deficiency*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D016923:Cell Death; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology
chemical_list: D052242:Adiponectin; D008070:Lipopolysaccharides; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D002118:Calcium; D020123:Sirolimus
keywords: Adiponectin; Apoptosis; Autophagy; Cardiac function; Endotoxemia; Inflammation