PERSONAL DE APOYO
MORELL malena
artículos
Título:
oxiCaMKII-dependent RyR2 Phosphorylation Mediates Cardiac Contractile Dysfunction Associated With Sepsis.
Autor/es:
SEPULVEDA MARISA; GONANO LUIS; VIOTTI MANUEL; MORELL MALENA
Revista:
CRITICAL CARE MEDICINE.
Editorial:
LIPPINCOTT WILLIAMS & WILKINS
Referencias:
Lugar: Philadelphia; Año: 2016
ISSN:
0090-3493
Resumen:
Objective: sepsis is associated with cardiac contractile dysfunction attributed to alterations in Ca2+ handling.We examined the subcellular mechanisms involved in SR Ca2+ loss that mediate altered Ca2+ handling and contractile dysfunction associated with sepsis.Design: Randomized controlled trial.Setting: Research laboratorySubjects: Male wild type (WT) and transgenic mice (TG)Interventions: We induced sepsis in mice using the colon ascendens stent peritonitis model (CASP).Measurements and results: 24hs after CASP surgery we observed that WT mice had significantly elevated pro-inflammatory cytokine levels, reduced ejection fraction (EF) and fractional shortening (FS) (EF% 54.76±0.67; FS% 27.53±0.50) compared to Sham controls (EF% 73.57±0.20; FS% 46.75±0.38). At the cardiac myocyte level, CASP cells showed reduced cell shortening, Ca2+ transient amplitude and SR Ca2+ content compared to Sham cardiomyocytes. CASP hearts showed a significant increase in oxidation-dependent calcium and calmodulin-dependent protein kinase II (CaMKII) activity which could be prevented by pretreating animals with the antioxidant Tempol. Pharmacological inhibition of CaMKII with 2.5µM KN93 prevented the decrease in cell shortening, Ca2+ transient amplitude and SR Ca2+ content in CASP myocytes. Contractile function was also preserved in CASP myocytes isolated from TG mice expressing a CaMKII inhibitory peptide (AC3-I) and in CASP myocytes isolated from mutant mice that have the RyR2 CaMKII-dependent phosphorylation site (Ser2814) mutated to alanine (S2814A). Furthermore, CASP S2814A mice showed preserved ejection fraction (EF) and fractional shortening (FS) (EF% 73.06±6.31; FS% 42.33±5.70) compared to Sham S2814A mice EF% 71.60±4.02; FS% 39.63±3.23). Results indicate that oxidation and subsequent activation of CaMKII has a causal role in the contractile dysfunction associated with sepsis. CaMKII, through phosphorylation of RyR2 would lead to Ca2+ leak from the SR, reducing SR Ca2+ content, Ca2+ transient amplitude and contractility. Development of organ specific CaMKII inhibitors may result a beneficial therapeutic strategy to ameliorate contractile dysfunction associated with sepsis.