Inhibition of CaMKII in mitochondria preserves endothelial barrier function after irradiation

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Iowa

Details

Original languageEnglish (US)
Pages (from-to)287-298
Number of pages12
JournalFree Radical Biology and Medicine
Volume146
StatusPublished - Jan 2020
Peer-reviewedYes

Abstract

Damage to the microvascular endothelium is an important part of normal tissue injury after radiation exposure and driven by the production of pro-oxidants. The Ca2+/calmodulin-dependent protein kinase II is present in the mitochondrial matrix (mitoCaMKII) where it regulates Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) and pro-oxidant production. Here, we demonstrate that radiation exposure disrupts endothelial cell barrier integrity in vitro, but can be abrogated by inhibition of mitoCaMKII, MCU, or opening of the mitochondrial transition pore. Scavenging of mitochondrial pro-oxidants with mitoTEMPO before, but not after irradiation, protected barrier function. Furthermore, markers of apoptosis and mitochondrial pro-oxidant production were elevated at 24 h following irradiation and abolished by mitoCaMKII inhibition. Endothelial barrier dysfunction was detected as early as 2 h after irradiation. Despite only mildly impaired mitochondrial respiration, the intracellular ATP levels were significantly reduced 4 h after irradiation and correlated with barrier function. MitoCaMKII inhibition improved intracellular ATP concentrations by increasing glycolysis. Finally, DNA double strand break repair and non-homologous end joining, two major drivers of ATP consumption after irradiation, were greatly increased but not significantly affected by mitoCaMKII inhibition. These findings support the hypothesis that mitoCaMKII activity is linked to mitochondrial pro-oxidant production, reduced ATP production, and loss of endothelial barrier function following irradiation. The inhibition of mitoCaMKII is a promising approach to limiting radiation-induced endothelial injury.

    Research areas

  • Calmodulin-dependent kinase II, Endotheliopathy, Endothelium, Mitochondria/mitochondrial Ca uniporter, Radiation

Citation formats

APA

Roy, S. J., Koval, O. M., Sebag, S. C., Ait-Aissa, K., Allen, B. G., Spitz, D. R., & Grumbach, I. M. (2020). Inhibition of CaMKII in mitochondria preserves endothelial barrier function after irradiation. Free Radical Biology and Medicine, 146, 287-298. https://doi.org/10.1016/j.freeradbiomed.2019.11.012

Harvard

Roy, SJ, Koval, OM, Sebag, SC, Ait-Aissa, K, Allen, BG, Spitz, DR & Grumbach, IM 2020, 'Inhibition of CaMKII in mitochondria preserves endothelial barrier function after irradiation', Free Radical Biology and Medicine, vol. 146, pp. 287-298. https://doi.org/10.1016/j.freeradbiomed.2019.11.012