title: Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis.
abstract: Sepsis is characterized by systematic inflammation where oxidative damage plays a key role in organ failure. This study was designed to examine the impact of the antioxidant metallothionein (MT) on lipopolysaccharide (LPS)-induced cardiac contractile and intracellular Ca(2+) dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Mechanical and intracellular Ca(2+) properties were examined in hearts from FVB and cardiac-specific MT overexpression mice treated with LPS. Oxidative stress, activation of mitogen-activated protein kinase pathways (ERK, JNK and p38), ER stress, autophagy and inflammatory markers iNOS and TNFalpha were evaluated. Our data revealed enlarged end systolic diameter, decreased fractional shortening, myocyte peak shortening and maximal velocity of shortening/relengthening as well as prolonged duration of relengthening in LPS-treated FVB mice associated with reduced intracellular Ca(2+) release and decay. LPS treatment promoted oxidative stress (reduced glutathione/glutathione disulfide ratio and ROS generation). Western blot analysis revealed greater iNOS and TNFalpha, activation of ERK, JNK and p38, upregulation of ER stress markers GRP78, Gadd153, PERK and IRE1alpha, as well as the autophagy markers Beclin-1, LCB3 and Atg7 in LPS-treated mouse hearts without any change in total ERK, JNK and p38. Interestingly, these LPS-induced changes in echocardiographic, cardiomyocyte mechanical and intracellular Ca(2+) properties, ROS, stress signaling and ER stress (but not autophagy, iNOS and TNFalpha) were ablated by MT. Antioxidant N-acetylcysteine and the ER stress inhibitor tauroursodeoxycholic acid reversed LPS-elicited depression in cardiomyocyte contractile function. LPS activated AMPK and its downstream signaling ACC in conjunction with an elevated AMP/ATP ratio, which was unaffected by MT. Taken together, our data favor a beneficial effect of MT in the management of cardiac dysfunction in sepsis.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Asli F
authors.initials: AF
authors.lastname: Ceylan-Isik
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Bingfang
authors.initials: B
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xiao
authors.forename: Guohai
authors.initials: G
authors.lastname: Su
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001696:Biomechanical Phenomena / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D007249:Inflammation / Q000150:complications; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D008668:Metallothionein; D000263:Adenylate Kinase; D002118:Calcium