Inhibiting Cardiac Mitochondrial Fatty Acid Oxidation Attenuates Myocardial Injury in a Rat Model of Cardiac Arrest.

Peng Wang,Qiulin Ge,Yunke Tan,Zitong Huang,Liming Pan,Fan Zhang,Fengqing Song,Lan Yao

doi:10.1155/2021/6622232

Abstract

Mitochondrial fatty acid oxidation (FAO) is involved in myocardial damage after cardiopulmonary resuscitation (CPR). This study is aimed at investigating the effect of inhibiting mitochondrial FAO on myocardial injury and the underlying mechanisms of postresuscitation myocardial dysfunction. Rats were induced, subjected to 8 min of ventricular fibrillation, and underwent 6 min of CPR. Rats with return of spontaneous circulation (ROSC) were randomly divided into the Sham group, CPR group, and CPR + Trimetazidine (TMZ) group. Rats in the CPR + TMZ group were administered TMZ (10 mg/kg) at the onset of ROSC via the right external jugular vein, while rats in the CPR group were injected with equivalent volumes of vehicle. The sham rats were only administered equivalent volumes of vehicle. We found that the activities of enzymes related to cardiac mitochondrial FAO were partly improved after ROSC. TMZ, as a reversible inhibitor of 3-ketoacyl CoA thiolase, inhibited myocardial mitochondrial FAO after ROSC. In the CPR + TMZ group, the levels of mitochondrial injury in cardiac tissue were alleviated following attenuated myocardial damage and oxidative stress after ROSC. In addition, the disorder of cardiac mitochondrial metabolism was ameliorated, and specifically, the superfluous succinate related to mitochondrial reactive oxygen species (ROS) generation was decreased by inhibiting myocardial mitochondrial FAO with TMZ administration after ROSC. In conclusion, in the early period after ROSC, inhibiting cardiac mitochondrial FAO attenuated excessive cardiac ROS generation and preserved myocardial function, probably by alleviating the dysfunction of cardiac mitochondrial metabolism in a rat model of cardiac arrest.

Highlights

Sudden cardiac arrest is a leading cause of mortality worldwide
The activities of enzymes related to mitochondrial fatty acid oxidation (FAO) were evaluated in the heart. 1 h after return of spontaneous circulation (ROSC), the activities of 3-ketoacyl CoA thiolase (3-KT) (Figure 2(a)), carnitine palmitoyltransferase 1 (CPT1) (Figure 2(b)), and acyl-CoA dehydrogenase (ACDH) (Figure 2(c)) were markedly elevated compared with the Sham group
3 h after ROSC, the activity of CPT1 (Figure 2(b)) remained higher, but there was no significant difference in the activities of 3-KT and ACDH (Figures 2(a) and 2(c))

Summary

Introduction

Sudden cardiac arrest is a leading cause of mortality worldwide. Despite the development of cardiopulmonary resuscitation (CPR) science and the increased rate of return of spontaneous circulation (ROSC), the survival rate in patients with sudden cardiac arrest after hospital discharge remains less than 10% [1, 2]. Deaths within the first 24 h of ROSC are typically associated with multiorgan system failure, especially due to postresuscitation myocardial dysfunction [3, 4]. It is widely believed that oxidative stress damage in the process of global myocardial ischemia/reperfusion after ROSC is the main factor linking cardiac arrest to postresuscitation myocardial dysfunction [5, 6]. Many studies have focused on how to mitigate cardiac oxidative injury after ROSC, there remains no effective therapy for clinical application. The generation of mitochondrial reactive oxygen species (ROS) is the main source of ROS and a crucial early driver of ischemia/reperfusion injury after ROSC [7, 8]. A large body of experimental literature supports that mitochondrial ETC inhibitors appear to attenuate myocardial oxidative injury during ischemia/reperfusion [11, 12].

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