期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 177, 期 -, 页码 370-380出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.10.035
关键词
Fatty acid metabolism; Myocardial infarction; PUFA; Acylcarnitine; Trimethyllysine; Gamma-butyrobetaine
资金
- Latvian Council of Science, project TRILYSOX [LZP-2018/1-0082]
- European Union [857394]
Deletion of the TMLHE gene in mice leads to reduced synthesis of long-chain acylcarnitines, resulting in decreased cardiac and mitochondrial damage, and a smaller infarct size. This study confirms that inhibiting the accumulation of ROS-increasing intermediates in fatty acid metabolism prevents damage during ischemia-reperfusion.
Increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage by stimulating ROS production. N6-trimethyllysine dioxygenase (TMLD) is the first enzyme in the carnitine/acylcarnitine biosynthesis pathway. Inactivation of the TMLHE gene (TMLHE KO) in mice is expected to limit long-chain acylcarnitine synthesis and thus induce a cardio- and mitochondria-protective phenotype. TMLHE gene deletion in male mice lowered acylcarnitine concentrations in blood and cardiac tissues by up to 85% and decreased fatty acid oxidation by 30% but did not affect muscle and heart function in mice. Metabolome profile analysis revealed increased levels of polyunsaturated fatty acids (PUFAs) and a global shift in fatty acid content from saturated to unsaturated lipids. In the risk area of ischemic hearts in TMLHE KO mouse, the OXPHOS-dependent respiration rate and OXPHOS coupling efficiency were fully preserved. Additionally, the decreased long-chain acylcarnitine synthesis rate in TMLHE KO mice prevented ischaemia-reperfusion-induced ROS production in cardiac mitochondria. This was associated with a 39% smaller infarct size in the TMLHE KO mice. The arrest of the acylcarnitine biosynthesis pathway in TMLHE KO mice prevents ischaemia-reperfusion-induced damage in cardiac mitochondria and decreases infarct size. These results confirm that the decreased accumulation of ROSincreasing fatty acid metabolism intermediates prevents mitochondrial and cardiac damage during ischaemiareperfusion.
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