title: AMP-activated protein kinase deficiency rescues paraquat-induced cardiac contractile dysfunction through an autophagy-dependent mechanism.
abstract: OBJECTIVE
  Paraquat, a quaternary nitrogen herbicide, is a highly toxic prooxidant resulting in multi-organ failure including the heart although the underlying mechanism still remains elusive. This study was designed to examine the role of the cellular fuel sensor AMP-activated protein kinase (AMPK) in paraquat-induced cardiac contractile and mitochondrial injury.
  
  
  RESULTS
  Wild-type and transgenic mice with overexpression of a mutant AMPK α2 subunit (kinase dead, KD), with reduced activity in both α1 and α2 subunits, were administered with paraquat (45 mg/kg) for 48 h. Paraquat elicited cardiac mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic diameter and reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, reduced cell survival, and overt mitochondrial damage (loss in mitochondrial membrane potential). In addition, paraquat treatment promoted phosphorylation of AMPK and autophagy. Interestingly, deficiency in AMPK attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) derangement. The beneficial effect of AMPK inhibition was associated with inhibition of the AMPK-TSC-mTOR-ULK1 signaling cascade. In vitro study revealed that inhibitors for AMPK and autophagy attenuated paraquat-induced cardiomyocyte contractile dysfunction.
  
  
  CONCLUSIONS
  Taken together, our findings revealed that AMPK may mediate paraquat-induced myocardial anomalies possibly by regulating the AMPK/mTOR-dependent autophagy.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming 82071.
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, Wyoming 82071 Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming 82071.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming 82071.
authors.forename: Sreejayan
authors.initials: S
authors.lastname: Nair
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming 82071.
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, Wyoming 82071 jren@uwyo.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D004452:Echocardiography; D005260:Female; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010269:Paraquat / Q000633:toxicity*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology
chemical_list: D006540:Herbicides; D055372:AMP-Activated Protein Kinases; D010269:Paraquat; D002118:Calcium
keywords: AMPK deficiency; autophagy; contractile function; myocardium; paraquat
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