Show simple item record

Authordc.contributor.authorSalas, Margarita A. 
Authordc.contributor.authorValverde, Carlos A. es_CL
Authordc.contributor.authorSánchez, Gina es_CL
Authordc.contributor.authorSaid, Matilde es_CL
Authordc.contributor.authorRodríguez, Jesica S. es_CL
Authordc.contributor.authorPortiansky, Enrique L. es_CL
Authordc.contributor.authorKaetzel, Marcia A. es_CL
Authordc.contributor.authorDedman, John R. es_CL
Authordc.contributor.authorDonoso Laurent, Paulina es_CL
Authordc.contributor.authorKranias, Evangelia G. es_CL
Authordc.contributor.authorMattiazzi, Alicia es_CL
Admission datedc.date.accessioned2010-07-01T16:12:19Z
Available datedc.date.available2010-07-01T16:12:19Z
Publication datedc.date.issued2010
Cita de ítemdc.identifier.citationJournal of Molecular and Cellular Cardiology 48 (2010) 1298–1306en_US
Identifierdc.identifier.otherdoi:10.1016/j.yjmcc.2009.12.015
Identifierdc.identifier.urihttps://repositorio.uchile.cl/handle/2250/128661
Abstractdc.description.abstractCa2+-calmodulin-dependent protein kinase II (CaMKII) plays an important role mediating apoptosis/ necrosis during ischemia-reperfusion (IR). We explored the mechanisms of this deleterious effect. Langendorff perfused rat and transgenic mice hearts with CaMKII inhibition targeted to sarcoplasmic reticulum (SR-AIP) were subjected to global IR. The onset of reperfusion increased the phosphorylation of Thr17 site of phospholamban, without changes in total protein, consistent with an increase in CaMKII activity. Instead, there was a proportional decrease in the phosphorylation of Ser2815 site of ryanodine receptors (RyR2) and the amount of RyR2 at the onset of reperfusion, i.e. the ratio Ser2815/RyR2 did not change. Inhibition of the reverse Na+/Ca2+exchanger (NCX) mode (KBR7943) diminished phospholamban phosphorylation, reduced apoptosis/necrosis and enhanced mechanical recovery. CaMKII-inhibition (KN-93), significantly decreased phospholamban phosphorylation, infarct area, lactate dehydrogenase release (LDH) (necrosis), TUNEL positive nuclei, caspase-3 activity, Bax/Bcl-2 ratio and Ca2+-induced mitochondrial swelling (apoptosis), and increased contractile recovery when compared with non-treated IR hearts or IR hearts pretreated with the inactive analog, KN-92. Blocking SR Ca2+ loading and release (thapsigargin/dantrolene), mitochondrial Ca2+ uniporter (ruthenium red/RU360), or mitochondrial permeability transition pore (cyclosporine A), significantly decreased infarct size, LDH release and apoptosis. SR-AIP hearts failed to show an increase in the phosphorylation of Thr17 of phospholamban at the onset of reflow and exhibited a significant decrease in infarct size, apoptosis and necrosis respect to controls. The results reveal an apoptotic-necrotic pathway mediated by CaMKII-dependent phosphorylations at the SR, which involves the reverse NCX mode and the mitochondria as trigger and end effectors, respectively, of the cascade.en_US
Patrocinadordc.description.sponsorshipThis work was supported by PICT 26117 (FONCyT), PIP 5300 and 02139 (CONICET) and FIRCA grant 5R03TW007713-02 to AM; PICT 1795 (FONCyT) to MAS; NIH, HL26057, HL64018, LEDUCQ Foundation to EGK, Fondecyt 1080497 and 1080481 to PD and GS.en_US
Lenguagedc.language.isoenen_US
Publisherdc.publisherELSEVIERen_US
Keywordsdc.subjectCaMKIIen_US
Títulodc.titleThe signalling pathway of CaMKII-mediated apoptosis and necrosis in the ischemia/reperfusion injuryen_US
Document typedc.typeArtículo de revista


Files in this item

Icon

This item appears in the following Collection(s)

Show simple item record