Abstract
Uncoupling protein 1 (UCP1) was found exclusively in the inner membranes of the mitochondria of brown adipose tissue (BAT). We found that UCP1 was also expressed in heart tissue and significantly upregulated in isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rat model. The present study is to determine the underlying mechanism involved in the UCP1 upregulation in ISO-induced AMI rat model. The Ucp1−/− rats were generated by CRISPR-Cas9 system and presented decreased BAT volume. 2-months old Sprague Dawley (SD) wild-type (WT) and Ucp1−/− rats were treated with ISO intraperitoneally 30 mg/kg once a day for 3 consecutive days to establish AMI model. In saline group, the echocardiographic parameters, serum markers of myocardial injury cardiac troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), oxidant malondialdehyde (MDA), antioxidant superoxide dismutase (SOD) or fibrosis were comparable between WT and Ucp1−/− rats. ISO treatment induced worse left ventricle (LV) hypertrophy, myocardial fibrosis, increased higher cTnI, CK-MB and MDA and decreased lower SOD level in Ucp1−/− rats compared with that of WT rats. Ucp1−/− rats also presented lower myocardial phosphocreatine (PCr)/ATP-ratio, which demonstrated worse cardiac energy regulation defect. ISO treatment induced the phosphorylation of AMP-activated protein kinase (AMPK) activation, subsequently the phosphorylation of mammalian target of rapamycin (mTOR) inhibition and peroxisome proliferators-activated receptor α (PPARα) activation in WT rats, whereas activation of AMPK/mTOR/PPARα pathways significantly inhibited in Ucp1−/− rats. To sum up, UCP1 knockout aggravated ISO-induced AMI by inhibiting AMPK/mTOR/PPARα pathways in rats. Increasing UCP1 expression in heart tissue may be a cytoprotective therapeutic strategy for AMI.
Highlights
Acute myocardial ischemia (AMI) is a leading cause of acute myocardial infarction which with high mortality (7%) and morbidity (22%) worldwide and is characterized by an acute condition of myocardial ischemic necrosis caused by the interruption in the supply of myocardial oxygen and nutrients (Meng et al 2018)
We analyzed the expression of Uncoupling protein 1 (UCP1) in heart tissues from WT rats treated with saline and ISO intraperitoneal injection, respectively, and the results indicated that UCP1 expression was increased significantly by 1.7-fold in heart tissues from ISO-induced AMI rat model compared with saline controls (n = 3 in the saline and ISO group, respectively, P \ 0.001, Fig. 1a, b)
We found that there was no significant difference in the levels of phosphor-adenosine monophosphate (AMP)-activated protein kinase (AMPK) and phosphor-mammalian target of rapamycin (mTOR) in WT and Ucp1-/- rats after saline treatment, while the level of phosphor-AMPK was significantly increased, and subsequently the level of phosphor-mTOR was decreased and phosphor-peroxisome proliferators-activated receptor a (PPARa) was increased in WT littermates after ISO treatment, whereas the activation of AMPK, inhibition of mTOR and activation of PPARa induced by ISO were significantly inhibited in Ucp1-/- rats (Fig. 5)
Summary
Acute myocardial ischemia (AMI) is a leading cause of acute myocardial infarction which with high mortality (7%) and morbidity (22%) worldwide and is characterized by an acute condition of myocardial ischemic necrosis caused by the interruption in the supply of myocardial oxygen and nutrients (Meng et al 2018). Intracellular energy metabolism is abnormal and oxidative stress increases with large reactive oxygen species (ROS) generation (Vanden Hoek et al 1997). It is well established that mitochondria are a main source of cellular ROS(Murphy, 2009) and mitochondrial ROS production is steeply dependent on electrochemical proton gradient (4p) (Cadenas, 2018) which drives adenosine triphosphate (ATP) synthesis by F0F1ATPase, correspondingly, control mitochondrial ROS generation has been identified as a cytoprotective strategy under conditions of oxidative stress. Proton leak increases the respiration rate, dissipates the 4p, induces partial mitochondrial oxidative phosphorylation uncoupling and generates heat instead of ATP, diminishing mitochondrial ROS production (Akhmedov et al 2015; Sack 2006)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
