CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
artículos
Título:
Calcium and Calmodulin-Dependent Protein Kinase II-Dependent Ryanodine Receptor Phosphorylation Mediates Cardiac Contractile Dysfunction Associated With Sepsis
Autor/es:
VIOTTI MANUEL; SEPÚLVEDA MARISA; LÓPEZ ALARCÓN MICAELA; MORELL MALENA; MEDEI EMILIANO; PEROBA RAMOS ISALIRA; VILA PETROFF MARTÍN; GONANO LUIS A.; BLANCO PAULA; BASTOS CARVALHO ADRIANA
Revista:
CRITICAL CARE MEDICINE.
Editorial:
LIPPINCOTT WILLIAMS & WILKINS
Referencias:
Lugar: Philadelphia; Año: 2016 vol. XX
ISSN:
0090-3493
Resumen:
Objectives: Sepsis is associated with cardiac contractile dysfunctionattributed to alterations in Ca2+ handling. We examined thesubcellular mechanisms involved in sarcoplasmic reticulum Ca2+loss that mediate altered Ca2+ handling and contractile dysfunctionassociated with sepsis.Design: Randomized controlled trial.Setting: Research laboratorySubjects: Male wild type and transgenic miceInterventions: We induced sepsis in mice using the colon ascendensstent peritonitis model.Measurements and Main Results: Twenty-four hours after colonascendens stent peritonitis surgery, we observed that wild typemice had significantly elevated proinflammatory cytokine levels,reduced ejection fraction, and fractional shortening (ejectionfraction %, 54.76 ± 0.67; fractional shortening %, 27.53 ± 0.50)compared with sham controls (ejection fraction %, 73.57 ± 0.20;fractional shortening %, 46.75 ± 0.38). At the cardiac myocytelevel, colon ascendens stent peritonitis cells showed reducedcell shortening, Ca2+ transient amplitude and sarcoplasmic reticulumCa2+ content compared with sham cardiomyocytes. Colonascendens stent peritonitis hearts showed a significant increasein oxidation-dependent calcium and calmodulin-dependent proteinkinase II activity, which could be prevented by pretreatinganimals with the antioxidant tempol. Pharmacologic inhibition ofcalcium and calmodulin-dependent protein kinase II with 2.5 μMof KN93 prevented the decrease in cell shortening, Ca2+ transientamplitude, and sarcoplasmic reticulum Ca2+ content in colonascendens stent peritonitis myocytes. Contractile function wasalso preserved in colon ascendens stent peritonitis myocytes isolatedfrom transgenic mice expressing a calcium and calmodulin-dependent protein kinase II inhibitory peptide (AC3-I) and incolon ascendens stent peritonitis myocytes isolated from mutantmice that have the ryanodine receptor 2 calcium and calmodulin-dependent protein kinase II-dependent phosphorylation site(serine 2814) mutated to alanine (S2814A). Furthermore, colonascendens stent peritonitis S2814A mice showed preservedejection fraction and fractional shortening (ejection fraction %,73.06 ± 6.31; fractional shortening %, 42.33 ± 5.70) comparedwith sham S2814A mice (ejection fraction %, 71.60 ± 4.02; fractionalshortening %, 39.63 ± 3.23).Conclusions: Results indicate that oxidation and subsequent activationof calcium and calmodulin-dependent protein kinase II hasa causal role in the contractile dysfunction associated with sepsis.Calcium and calmodulin-dependent protein kinase II, throughphosphorylation of the ryanodine receptor would lead to Ca2+ leakfrom the sarcoplasmic reticulum, reducing sarcoplasmic reticulumCa2+ content, Ca2+ transient amplitude and contractility. Developmentof organ-specific calcium and calmodulin-dependent proteinkinase II inhibitors may result in a beneficial therapeutic strategyto ameliorate contractile dysfunction associated with sepsis.