Document Detail


SERCA Cys674 sulphonylation and inhibition of L-type Ca2+ influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis.
MedLine Citation:
PMID:  23934853     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP [produced by soluble guanylyl cyclase (sGC)] versus oxidative posttranslational modifications of Ca(2+) transporters. C57BL/6 mice [wild-type (WT) mice] were administered lipopolysaccharide (LPS; 25 μg/g ip) and euthanized 12 h later. Cardiomyocyte sarcomere shortening and Ca(2+) transients (ΔCai) were depressed in LPS-challenged mice versus baseline. The time constant of Ca(2+) decay (τCa) was prolonged, and sarcoplasmic reticulum Ca(2+) load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of sarco(endo)plasmic Ca(2+)-ATPase (SERCA). L-type Ca(2+) channel current (ICa,L) was also decreased after LPS challenge, whereas Na(+)/Ca(2+) exchange activity, ryanodine receptors leak flux, or myofilament sensitivity for Ca(2+) were unchanged. All Ca(2+)-handling abnormalities induced by LPS (the decrease in sarcomere shortening, ΔCai, CaSR, ICa,L, and τCa prolongation) were more pronounced in mice deficient in the sGC main isoform (sGCα1(-/-) mice) versus WT mice. LPS did not alter the protein expression of SERCA and phospholamban in either genotype. After LPS, phospholamban phosphorylation at Ser(16) and Thr(17) was unchanged in WT mice and was increased in sGCα1(-/-) mice. LPS caused sulphonylation of SERCA Cys(674) (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1(-/-) versus WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in L-type Ca(2+) channel function and oxidative posttranslational modifications of SERCA Cys(674), with the latter (at least) being opposed by sGC-released cGMP.
Authors:
Ion A Hobai; Emmanuel S Buys; Justin C Morse; Jessica Edgecomb; Eric H Weiss; Antonis A Armoundas; Xiuyun Hou; Alok R Khandelwal; Deborah A Siwik; Peter Brouckaert; Richard A Cohen; Wilson S Colucci
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-08-09
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  305     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-16     Completed Date:  2013-12-06     Revised Date:  2014-10-15    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1189-200     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*
Calcium Channels, L-Type / metabolism*
Calcium-Binding Proteins / metabolism
Cyclic GMP / biosynthesis
Cysteine / metabolism
Endotoxemia / metabolism*
Guanylate Cyclase / genetics
Heart / physiopathology*
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium / metabolism
Myocytes, Cardiac / metabolism*
Protein Processing, Post-Translational / physiology*
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcomeres
Sarcoplasmic Reticulum / metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
Sodium-Calcium Exchanger / metabolism
Grant Support
ID/Acronym/Agency:
HL-061639/HL/NHLBI NIH HHS; HL-064750/HL/NHLBI NIH HHS; HL-31607/HL/NHLBI NIH HHS; K08 GM096082/GM/NIGMS NIH HHS; K08-GM-096082/GM/NIGMS NIH HHS; N01-HV-28178/HV/NHLBI NIH HHS; T32-GM-007592/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Calcium Channels, L-Type; 0/Calcium-Binding Proteins; 0/Lipopolysaccharides; 0/Ryanodine Receptor Calcium Release Channel; 0/Sodium-Calcium Exchanger; 0/phospholamban; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases; EC 4.6.1.2/Guanylate Cyclase; H2D2X058MU/Cyclic GMP; K848JZ4886/Cysteine; SY7Q814VUP/Calcium
Comments/Corrections

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