Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.

Abstract

OBJECTIVES:

Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation and the use of therapeutic hypothermia. Dynamin-related protein 1, a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that dynamin-related protein 1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest.

DESIGN:

Laboratory investigation.

SETTING:

University laboratory.

INTERVENTIONS:

Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-minute KCl-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of Mdivi-1 (0.24 mg/kg), a small molecule dynamin-related protein 1 inhibitor or vehicle (dimethyl sulfoxide).

MEASUREMENTS AND MAIN RESULTS:

Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by dynamin-related protein 1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during cardiopulmonary resuscitation inhibited dynamin-related protein 1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (116 ± 4 vs 143 ± 7 s; p < 0.001) during cardiopulmonary resuscitation and enhanced myocardial performance post-return of spontaneous circulation. These improvements were associated with significant increases in survival (65% vs 33%) and improved neurological scores up to 72 hours post cardiac arrest.

CONCLUSIONS:

Post-cardiac arrest inhibition of dynamin-related protein 1 improves time to return of spontaneous circulation and myocardial hemodynamics, resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.

• Authors: Willard W Sharp, David G Beiser, Yong Hu Fang, Mei Han, Lin Piao, Justin Varughese, Stephen L Archer
• Journal: Critical care medicine (Crit Care Med) Vol. 43 Issue 2 Pg. e38-47 (Feb 2015) ISSN: 1530-0293 [Electronic] United States
• PMID: 25599491 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
• Quinazolinones
• Dynamins
• Aconitate Hydratase

Topics

• Aconitate Hydratase (metabolism)
• Animals
• Disease Models, Animal
• Dynamins (antagonists & inhibitors)
• Female
• Heart Arrest (metabolism)
• Immunoblotting
• Mice
• Mice, Inbred C57BL
• Microscopy, Electron, Transmission
• Mitochondrial Dynamics (drug effects, physiology)
• Quinazolinones (pharmacology)
• Random Allocation