Abstract
Abstract 16059: Histidyl Dipeptide Carnosine Imparts Cardiac Protection During Ischemia Reperfusion Injury by Sequestering Lipid Peroxidation Products and Buffering Intracellular pH
Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A16059-A16059
11/06/2018
Abstract
Myocardial ischemia reperfusion (I/R) injury is a complex pathophysiological condition marked by oxidative stress, excessive generation of lipid peroxidation products, such as 4hydroxynonenal (4HNE) and pH imbalance. Although there are individual interventions to address each I/R-induced imbalance, a strategy to simultaneously target different mediators of injury is needed. Carnosine (β-alanine-histidine) is a histidyl dipeptide synthesized by carnosine sythetase (ATPGD1), present in high concentrations in the skeletal muscle and heart, that scavenges lipid peroxidation products and buffers intracellular pH. Based on these biochemical properties, we hypothesized that enhancing cardiac carnosine levels could limit I/R injury. WT C57 mice treated with carnosine (10-gm/L) or β-alanine (20-gm/L) in water for 7 days had 3-4-fold higher cardiac carnosine levels compared with untreated mice. When subjected to 30 min of left coronary artery occlusion followed by 24 h of reperfusion, the infarct size was 38±2% in the untreated and 25±3% in the carnosine and 17±3% in the β-alanine fed mice (p<0.05 vs untreated). To test for a myocyte-specific protection, α-MHC promoter driven ATPGD1 mice were generated, which had normal cardiac function, enhanced cardiac carnosine levels (20-50 fold) and decreased infarct size (38±2%) compared with WT mice (59±3%; p<0.05) after 30 min of ischemia and 24 h of reperfusion. To assess the mechanisms of protection, glycolytic rates measured by C lactate efflux during low flow ischemia (LFI) showed 2-3-fold increase in ATPGD1-transgenic (Tg) compared with WT mice hearts. Comparison of global metabolomic profile between the WT and ATPGD1Tg heart after 5 min of global ischemia showed that the highest pathway impact was on glycolysis. Acrolein and 4HNE protein adducts were decreased in the ATPGD1-Tg ischemic compared with the WT ischemic hearts. Moreover, acrolein- and 4HNE-induced hypercontractures were delayed significantly in the ATPGD1-Tg or carnosine-pretreated isolated cardiomyocytes. High energy phosphates measured by P-NMR spectroscopy showed that the decline of ATP, phosphocreatine and pHi was slower and the recovery was significantly better in the ATPGD1-Tg compared with WT hearts during LFI and reperfusion, respectively. Collectively, our results suggest that carnosine has the potential to target multiple mediators of I/R injury and thus an effective therapeutic strategy for cardioprotection.
Details
- Title: Subtitle
- Abstract 16059: Histidyl Dipeptide Carnosine Imparts Cardiac Protection During Ischemia Reperfusion Injury by Sequestering Lipid Peroxidation Products and Buffering Intracellular pH
- Creators
- Jingjing Zhao - University of LouisvilleYiru Guo - University of LouisvilleDaniel Conklin - University of LouisvilleLuping Guo - University of LouisvilleDetlef Obal - University of LouisvilleDheeraj Posa - University of LouisvilleDavid Hoetker - University of LouisvilleAminul Prodhan - University of LouisvilleXiang Zhang - University of LouisvilleAruni Bhatnagar - University of LouisvilleShahid Baba - University of Louisville
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A16059-A16059
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/06/2018
- Academic Unit
- Anesthesia
- Record Identifier
- 9984696834702771
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