TY - JOUR
T1 - Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus
AU - Hong, Zhigang
AU - Kutty, Shelby
AU - Toth, Peter T.
AU - Marsboom, Glenn
AU - Hammel, James M.
AU - Chamberlain, Carolyn
AU - Ryan, John J.
AU - Zhang, Hannah J.
AU - Sharp, Willard W.
AU - Morrow, Erik
AU - Trivedi, Kalyani
AU - Weir, E. Kenneth
AU - Archer, Stephen L.
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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.
AB - 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.
KW - Mdivi-1 compound
KW - green fluorescent protein
KW - mitochondrial dynamics
KW - oxygen sensing
KW - patent ductus arteriosus
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UR - http://www.scopus.com/inward/citedby.url?scp=84874779519&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.111.300285
DO - 10.1161/CIRCRESAHA.111.300285
M3 - Article
C2 - 23334860
AN - SCOPUS:84874779519
SN - 0009-7330
VL - 112
SP - 802
EP - 815
JO - Circulation research
JF - Circulation research
IS - 5
ER -