In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 112, No. 5 ( 2013-03), p. 802-815
Abstract:
Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial P O 2 -dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O 2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O 2 increases mitochondrial-derived H 2 O 2 , which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. Objective: The purpose of this study was to determine whether mitochondrial fission is crucial for O 2 -induced DA constriction and closure. Methods and Results: Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O 2 -induced constriction and closure. O 2 rapidly ( 〈 5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H 2 O 2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates P O 2 -induced increases in mitochondrial-derived H 2 O 2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O 2 -induced constriction (without altering the response to phenylephrine or KCl) and preventing O 2 -induced increases in oxidative metabolism, cytosolic calcium, and ductal smooth muscle cells proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model. Conclusions: Mitochondrial fission is an obligatory, early step in mammalian O 2 sensing and offers a promising target for modulating DA patency.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.111.300285
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2013
detail.hit.zdb_id:
1467838-X
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