SERCA Cys674sulphonylation and inhibition of L-type Ca2+influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis

Autor: Deborah A. Siwik, Eric H. Weiss, Jessica Edgecomb, Ion A. Hobai, Xiuyun Hou, Antonis A. Armoundas, Peter Brouckaert, Richard A. Cohen, Alok R. Khandelwal, Emmanuel S. Buys, Justin C. Morse, Wilson S. Colucci
Rok vydání: 2013
Předmět:
Lipopolysaccharides
Male
Sarcomeres
medicine.medical_specialty
SERCA
Calcium Channels
L-Type
Physiology
medicine.disease_cause
Sodium-Calcium Exchanger
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Nitric oxide
Contractility
Mice
chemistry.chemical_compound
Physiology (medical)
Internal medicine
Calcium-binding protein
medicine
Animals
Myocytes
Cardiac
Cysteine
Cyclic GMP
Mice
Knockout
Sodium-calcium exchanger
Cardiac Excitation and Contraction
Chemistry
Myocardium
Endoplasmic reticulum
Calcium-Binding Proteins
Heart
Ryanodine Receptor Calcium Release Channel
medicine.disease
Endotoxemia
Mice
Inbred C57BL
Sarcoplasmic Reticulum
Endocrinology
Guanylate Cyclase
Heart failure
cardiovascular system
Calcium
Cardiology and Cardiovascular Medicine
Protein Processing
Post-Translational
Oxidative stress
Zdroj: American Journal of Physiology-Heart and Circulatory Physiology. 305:H1189-H1200
ISSN: 1522-1539
0363-6135
DOI: 10.1152/ajpheart.00392.2012
Popis: 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 Ca2+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 Ca2+transients (ΔCai) were depressed in LPS-challenged mice versus baseline. The time constant of Ca2+decay (τCa) was prolonged, and sarcoplasmic reticulum Ca2+load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of sarco(endo)plasmic Ca2+-ATPase (SERCA). L-type Ca2+channel current ( ICa,L) was also decreased after LPS challenge, whereas Na+/Ca2+exchange activity, ryanodine receptors leak flux, or myofilament sensitivity for Ca2+were unchanged. All Ca2+-handling abnormalities induced by LPS (the decrease in sarcomere shortening, ΔCai, CaSR, ICa,L, and τCaprolongation) 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 Ser16and Thr17was unchanged in WT mice and was increased in sGCα1−/−mice. LPS caused sulphonylation of SERCA Cys674(as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1−/−versus WT mice. Taken together, these results suggest that cardiac Ca2+dysregulation in endotoxemic mice is mediated by a decrease in L-type Ca2+channel function and oxidative posttranslational modifications of SERCA Cys674, with the latter (at least) being opposed by sGC-released cGMP.
Databáze: OpenAIRE
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