In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 305, No. 8 ( 2013-10-15), p. H1189-H1200
Abstract:
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 (ΔCa i ) were depressed in LPS-challenged mice versus baseline. The time constant of Ca 2+ decay (τ Ca ) was prolonged, and sarcoplasmic reticulum Ca 2+ load (Ca SR ) 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 ( I Ca,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, ΔCa i , Ca SR , I Ca,L , and τ Ca prolongation) were more pronounced in mice deficient in the sGC main isoform (sGCα 1 −/− 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 sGCα 1 −/− mice. LPS caused sulphonylation of SERCA Cys 674 (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα 1 −/− 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.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00392.2012
Language:
English
Publisher:
American Physiological Society
Publication Date:
2013
detail.hit.zdb_id:
1477308-9
SSG:
12
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