Cellular injury from oxygen and nutrient deprivation (ischemic injury) occurs following heart attacks and strokes and is a major cause of death and disability. Cooling (hypothermia) patients to slow metabolism and limit cellular injury from ischemic injury is done to protect the heart and brain in cardiac surgery and following cardiac arrest. Inducing hypothermia is physically difficult and time consuming particularly in emergent situations, creating a barrier to its broader use. In addition, there is a large need to optimize the timing and depth of hypothermia for cellular protection while investigating the mechanisms of how hypothermia protects cells from injury. This project attempts to overcome these barriers by testing a novel chemical found in the blood stream of hibernating animals that induces torpor (hypo-metabolism/hypothermia) within minutes. Specifically, this project tests the hypothesis that pharmacological induction of torpor/hypothermia with 5?adenosine monophosphate (AMP) will improve post-CA outcomes by simultaneously activating AMP activated kinase (AMPK), while inhibiting the mitochondrial fission protein Dynamin related protein 1 (Drp1), thereby reversing myocardial stunning through improved mitochondrial and metabolic function. My preliminary data demonstrate that this chemical, 5?AMP rapidly induces hypothermia and cardioprotection within minutes of administration.
Aim 1 tests the effects of 5?AMP on improving cardiac arrest outcomes in multiple models of ischemia/reperfusion injury, while optimizing the conditions of hypothermia.
Aim 2 tests whether the effects of 5?AMP are mediated by AMPK through the use of mice with genetically attenuated or overexpressing AMPK. Finally, Aim 3 determines whether Drp1 expression is necessary for post-cardiac arrest mitochondrial and myocardial dysfunction. Success of this research will establish a new method for rapidly inducing hypothermia while identifying AMPK and Drp1 as new therapeutic targets for post cardiac arrest and ischemic injury.
Survival from sudden cardiac arrest is poor, but is improved by post-cardiac arrest induction of hypothermia. Strategies to physically induce hypothermia are difficult to implement and uncertainties exist as to the optimal timing and temperature for post-cardiac arrest hypothermia. This project investigates an alternative strategy of inducing hypothermia by inducing a state of hypo-metabolism (torpor/hibernation) pharmacologically to produce improved survival following cardiac arrest.
|Pillai, Vinodkumar B; Kanwal, Abhinav; Fang, Yong Hu et al. (2017) Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 8:34082-34098|
|Tian, Lian; Neuber-Hess, Monica; Mewburn, Jeffrey et al. (2017) Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension. J Mol Med (Berl) 95:381-393|
|Piao, Lin; Fang, Yong-Hu; Kubler, Manfred M et al. (2017) Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest. PLoS One 12:e0185046|