Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission.
Mitochondrial fission, regulated by dynamin-related protein-1 (Drp1), is a newly recognized determinant of mitochondrial function, but its contribution to left ventricular (LV) impairment following ischemia-reperfusion (IR) injury is unknown. We report that Drp1 activation during IR results in LV dysfunction and that Drp1 inhibition is beneficial. In both isolated neonatal murine cardiomyocytes and adult rat hearts (Langendorff preparation) mitochondrial fragmentation and swelling occurred within 30 min of IR. Drp1-S637 (serine 637) dephosphorylation resulted in Drp1 mitochondrial translocation and increased mitochondrial fission. The Drp1 inhibitor Mdivi-1 preserved mitochondrial morphology, reduced cytosolic calcium, and prevented cell death. Drp1 siRNA similarly preserved mitochondrial morphology. In Langendorff hearts, Mdivi-1 reduced mitochondrial reactive oxygen species, improved LV developed pressure (92±5 vs. 28±10 mmHg, P<0.001), and lowered LV end diastolic pressure (10±1 vs. 86±13 mmHg, P<0.001) following IR. Mdivi-1 was protective if administered prior to or following ischemia. Because Drp1-S637 dephosphorylation is calcineurin sensitive, we assessed the effects of a calcineurin inhibitor, FK506. FK506 treatment prior to IR prevented Drp1-S637 dephosphorylation and preserved cardiac function. Likewise, therapeutic hypothermia (30°C) inhibited Drp1-S637 dephosphorylation and preserved mitochondrial morphology and myocardial function. Drp1 inhibition is a novel strategy to improve myocardial function following IR.
1Section of Emergency Medicine, Department of Medicine, 5841 S. Maryland Ave., MC 5068, Chicago, IL 60637, USA. wsharp@medicine.bsd.uchicago.edu.
Willard W
WW
Sharp
Yong Hu
YH
Fang
Mei
M
Han
Hannah J
HJ
Zhang
Zhigang
Z
Hong
Alexandra
A
Banathy
Erik
E
Morrow
John J
JJ
Ryan
Stephen L
SL
Archer
D000818:Animals; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D052999:Quinazolinones / Q000494:pharmacology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology
C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D052999:Quinazolinones; D034741:RNA, Small Interfering; C486391:Dnm1l protein, mouse; D034281:Dynamins; D016559:Tacrolimus
IR; Mdivi-1; calcineurin; cardiac arrest; reactive oxygen species