INVESTIGADORES
MATTIAZZI Ramona Alicia
artículos
Título:
CAMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion
Autor/es:
DI CARLO MN; .SAID M, .; LING H; VALVERDE CA,; DE GIUSTI V; SOMESSE, L, .; PALOMEQUE J; AIELLO EA; SKAPURA D; RINALDI G; RESPRESS J; HELLER BROWN J; SALAS M; MATTIAZZI A
Revista:
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Editorial:
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2014 vol. 74 p. 274 - 283
ISSN:
0022-2828
Resumen:
Ca2+-calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R).Moreover, inhibition
of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum(SR) prevents CaMKII-induced I/R
damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain
unclear. In the present study we aimed to dissect the role of the two main substrates of CaMKII at the SR
level, phospholamban (PLN) and ryanodine receptors (RyR2), in CaMKII-dependent I/R injury. In mouse hearts
subjected to global I/R (45/120 min), phosphorylation of the primary CaMKII sites, S2814 on cardiac RyR2 and
of T17 on PLN, significantly increased at the onset of reperfusion whereas PKA-dependent phosphorylation of
RyR2 and PLN did not change. Similar results were obtained in vivo, in mice subjected to regional myocardial
I/R (1/24 h). Knock-in mice with an inactivated serine 2814 phosphorylation site on RyR2 (S2814A) significantly
improved post-ischemic mechanical recovery, reduced infarct size and decreased apoptosis. Conversely, knockin
mice, in which CaMKII site of RyR2 is constitutively activated (S2814D), significantly increased infarct size and
exacerbated apoptosis. In S2814A and S2814D mice subjected to regional myocardial ischemia, infarct size was
also decreased and increased respectively. Transgenic mice with double-mutant non-phosphorylatable PLN
(S16A/T17A) in the PLN knockout background (PLNDM) also showed significantly increased post-ischemic cardiac
damage. This effect cannot be attributed to PKA-dependent PLN phosphorylation andwas not due to the enhanced
L-type Ca2+ current, present in these mice. Our results reveal a major role for the phosphorylation of
S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent
increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage.