CaMKII-dependent ryanodine receptor phosphorylation mediates sepsis-induced cardiomyocyte apoptosis

SEPULVEDA MN; BURGOS JI; CIOCCI PARDO, A; GONZÁLEZ ARBELÁEZ LF; MOSCA SM; VILA PETROFF M

Journal of Cellular and Molecular Medicine.

Wiley editorial Library

Año: 2020

Sepsis is associated with cardiac dysfunction, which is at least in part due to cardiomyocyteapoptosis. However, the underlying mechanisms are far from being understood.Using the colon ascendens stent peritonitis mouse model of sepsis (CASP), weexamined the subcellular mechanisms that mediate sepsis-induced apoptosis. Wildtype(WT) CASP mice hearts showed an increase in apoptosis respect to WT-Sham.CASP transgenic mice expressing a CaMKII inhibitory peptide (AC3-I) were protectedagainst sepsis-induced apoptosis. Dantrolene, used to reduce ryanodine receptor(RyR) diastolic sarcoplasmic reticulum (SR) Ca2+ release, prevented apoptosis in WTCASP.To examine whether CaMKII-dependent RyR2 phosphorylation mediates diastolicCa2+ release and apoptosis in sepsis, we evaluated apoptosis in mutant micehearts that have the CaMKII phosphorylation site of RyR2 (Serine 2814) mutated toAlanine (S2814A). S2814A CASP mice did not show increased apoptosis. Consistentwith RyR2 phosphorylation-dependent enhancement in diastolic SR Ca2+ releaseleading to mitochondrial Ca2+ overload, mitochondrial Ca2+ retention capacity wasreduced in mitochondria isolated from WT-CASP compared to Sham and this reductionwas absent in mitochondria from CASP S2814A or dantrolene-treated mice. Weconclude that in sepsis, CaMKII-dependent RyR2 phosphorylation results in diastolicCa2+ release from SR which leads to mitochondrial Ca2+ overload and apoptosis.