Journal
VASCULAR PHARMACOLOGY
Volume 87, Issue -, Pages 209-218Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2016.09.010
Keywords
Carbon monoxide; Endothelial nitric oxide synthase; Calcium; Akt
Categories
Funding
- National Science Council, Taiwan [102-2320-B-415-002-MY3]
- Chiayi Christian Hospital [R105-22]
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The production of nitric oxide (NO) by endothelial NO synthase (eNOS) plays a major role in maintaining vascular homeostasis. This study elucidated the potential role of carbon monoxide (CO)-releasing molecules (CORMs) in NO production and explored the underlying mechanisms in endothelial cells. We observed that 25 mu M CORM-2 could increase NO production and stimulate an increase in the intracellular Ca2+ level. Furthermore, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetra acetic acid caused CORM-2-induced NO production, which was abolished by 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), indicating that intracellular Ca2+ release plays a major role in eNOS activation. The inhibition of the 1P3 receptor diminished the CORM-2-induced intracellular Ca2+ increase and NO production. Furthermore, CORM-2 induced eNOS Ser(1179) phosphorylation and eNOS dimerization, but it did not alter eNOS expression. CORM-2 (25 mu M) also prolonged Akt phosphorylation, lasting for at least 12 h. Pretreatment with phosphatidylinositol 3-kinase inhibitors (wortmannin or LY294002) inhibited the increases in NO production and phosphorylation but did not affect eNOS dimerization. CORM-2-induced eNOS Ser(1179) phosphorylation was intracellularly calcium-dependent, because pretreatment with an intracellular Ca2+ chelator (BAPTA-AM) inhibited this process. Although CORM-2 increases intracellular reactive oxygen species (ROS), pretreatment with antioxidant enzyme catalase and N-acetyl-cysteine did not abolish the CORM-2-induced eNOS activity or phosphorylation, signifying that ROS is not involved in this activity. Hence, CORM-2 enhances eNOS activation through intracellular calcium release, Akt phosphorylation, and eNOS dimerization. (C) 2016 Elsevier Inc All rights reserved.
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