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Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.

Abstract：

RATIONALE:Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-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, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, 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 O2-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 O2-induced constriction and closure. O2 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 H2O2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitochondrial-derived H2O2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-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 O2 sensing and offers a promising target for modulating DA patency.

journal_name

Circ Res

journal_title

Circulation research

authors

Hong Z,Kutty S,Toth PT,Marsboom G,Hammel JM,Chamberlain C,Ryan JJ,Zhang HJ,Sharp WW,Morrow E,Trivedi K,Weir EK,Archer SL

doi

10.1161/CIRCRESAHA.111.300285

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

802-15

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.111.300285

journal_volume

112

pub_type

杂志文章

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Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.