| First Author | Kreitmeier KG | Year | 2021 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 320 |
| Issue | 3 | Pages | H1199-H1212 |
| PubMed ID | 33449853 | Mgi Jnum | J:304101 |
| Mgi Id | MGI:6513756 | Doi | 10.1152/ajpheart.00040.2020 |
| Citation | Kreitmeier KG, et al. (2021) CaMKIIdelta Met281/282 oxidation is not required for recovery of calcium transients during acidosis. Am J Physiol Heart Circ Physiol 320(3):H1199-H1212 |
| abstractText | CaMKII is needed for the recovery of Ca(2+) transients during acidosis but also mediates postacidic arrhythmias. CaMKIIdelta can sustain its activity following Met281/282 oxidation. Increasing cytosolic Na(+) during acidosis as well as postacidic pH normalization should result in prooxidant conditions within the cell favoring oxidative CaMKIIdelta activation. We tested whether CaMKIIdelta activation through Met281/282 oxidation is involved in recovery of Ca(2+) transients during acidosis and promotes cellular arrhythmias post-acidosis. Single cardiac myocytes were isolated from a well-established mouse model in which CaMKIIdelta was made resistant to oxidative activation by knock-in replacement of two oxidant-sensitive methionines (Met281/282) with valines (MM-VV). MM-VV myocytes were exposed to extracellular acidosis (pHo 6.5) and compared to wild type (WT) control cells. Full recovery of Ca(2+) transients was observed in both WT and MM-VV cardiac myocytes during late-phase acidosis. This was associated with comparably enhanced sarcoplasmic reticulum Ca(2+) load and preserved CaMKII specific phosphorylation of phospholamban at Thr17 in MM-VV myocytes. CaMKII was phosphorylated at Thr287, but not Met281/282 oxidized. In line with this, postacidic cellular arrhythmias occurred to a similar extent in WT and MM-VV cells, whereas inhibition of CaMKII using AIP completely prevented recovery of Ca(2+) transients during acidosis and attenuated postacidic arrhythmias in MM-VV cells. Using genetically altered cardiomyocytes with cytosolic expression of redox-sensitive green fluorescent protein-2 coupled to glutaredoxin 1, we found that acidosis has a reductive effect within the cytosol of cardiac myocytes despite a significant acidosis-related increase in cytosolic Na(+). Our study shows that activation of CaMKIIdelta through Met281/282 oxidation is neither required for recovery of Ca(2+) transients during acidosis nor relevant for postacidic arrhythmogenesis in isolated cardiac myocytes. Acidosis reduces the cytosolic glutathione redox state of isolated cardiac myocytes despite a significant increase in cytosolic Na(+). Pharmacological inhibition of global CaMKII activity completely prevents recovery of Ca(2+) transients and protects from postacidic arrhythmias in MM-VV myocytes, which confirms the relevance of CaMKII in the context of acidosis.NEW & NOTEWORTHY The current study shows that activation of CaMKIIdelta through Met281/282 oxidation is neither required for CaMKII-dependent recovery of Ca(2+) transients during acidosis nor relevant for the occurrence of postacidic cellular arrhythmias. Despite a usually prooxidant increase in cytosolic Na(+), acidosis reduces the cytosolic glutathione redox state within cardiac myocytes. This novel finding suggests that oxidation of cytosolic proteins is less likely to occur during acidosis. |
