Abstract
Abstract 17415: Mitochondrial Ca2+/Calmodulin-Dependent Kinase II Inhibition Changes the Calcium Homeostasis in the Endothelium and Decreases the Vascular Relaxation in Mesenteric Arteries
Circulation (New York, N.Y.), Vol.142(Suppl_3), pp.A17415-A17415
11/17/2020
DOI: 10.1161/circ.142.suppl_3.17415
Abstract
Introduction:
The Ca2+/Calmodulin-dependent Kinase II (CaMKII) is present in mitochondria and cytosol. In mitochondria, it regulates the mitochondrial Ca
2+
uptake via the mitochondrial Ca2+ uniporter. Since endothelial nitric oxide synthase activity is regulated by intracellular [Ca2+], we hypothesized that it affects cytosolic Ca2+, NO production and ACh-dependent vasodilation.
Hypothesis:
Inhibition of mitochondrial CaMKII in endothelium increases the cytosolic [Ca2+], and decreases vasorelaxation by Acetylcholine.
Methods:
CaMKII in mitochondria was inhibited through expression of the mitochondria-targeted CaMKII inhibitor peptide (mito-CaMKIIN) in a novel transgenic mouse model (endo-mtCaMKIIN) in endothelial cells only or delivered by adenoviral transduction (Ad-mtCaMKIIN) in human Aortic Endothelium cells (HAEC). In HAEC, cytosolic Ca2+ levels (by FURA-2 AM), eNOS activation and NOx levels were measured.
Results:
The basal Ca2+ levels were higher in the cytosol of mitoCaMKIIN cells (1.08 ± 0.02 Fura-2 ratio normalized by control, p<0.05). Thapsigargin-induced ER Ca
2+
release was significantly higher with mitoCaMKIIN (AUC 0.252 ± 0.027 versus 0.112 ± 0.01275, p<0.05), whereas cytosolic Ca
2+
levels after ACh were reduced (AUC 0.191 ± 0.025 versus 0.435 ± 0.054). Higher levels of phosphorylation of eNOS at Ser1177 and Thr495 sites were seen at baseline. The concentration-response curve of vascular relaxation to acetylcholine and SNP shifted to the right (p<0.05) in mesenteric resistance artery of mitoCaMKIIN mice.
Conclusions:
The inhibition of mitochondrial CaMKII in the endothelium increases the cytosolic levels, endoplasmic reticulum storage of calcium and eNOS phosphorylation. However, there are lower calcium release and lower sensitivity to acetylcholine and SNP.
Details
- Title: Subtitle
- Abstract 17415: Mitochondrial Ca2+/Calmodulin-Dependent Kinase II Inhibition Changes the Calcium Homeostasis in the Endothelium and Decreases the Vascular Relaxation in Mesenteric Arteries
- Creators
- Celio Damacena De Angelis - University of IowaDaniel W Nuno - University of IowaOlha Koval - Iowa City, IAKathryn G Lamping - University of IowaIsabella M Grumbach - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.142(Suppl_3), pp.A17415-A17415
- DOI
- 10.1161/circ.142.suppl_3.17415
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/17/2020
- Academic Unit
- Cardiovascular Medicine; Internal Medicine; Radiation Oncology
- Record Identifier
- 9984362356502771
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