肉碱
棕榈酰肉碱
线粒体
氧化磷酸化
内科学
化学
生物化学
膜间隙
内分泌学
缺血
辅酶A
肉碱O-棕榈酰转移酶
β氧化
生物
新陈代谢
医学
酶
大肠杆菌
细菌外膜
还原酶
基因
作者
Edgars Liepinsh,Marina Makrecka‐Kuka,Kristine Volska,Janis Kuka,Elīna Makarova,U. Antone,Eduards Sevostjanovs,Reinis Vilšķe̅rsts,Arnis Strods,Kaspars Tārs,Maija Dambrova
摘要
The accumulation of long-chain fatty acids (FAs) and their CoA and carnitine esters is observed in the ischaemic myocardium after acute ischaemia/reperfusion. The aim of the present study was to identify harmful FA intermediates and their detrimental mechanisms of action in mitochondria and the ischaemic myocardium. In the present study, we found that the long-chain acyl-CoA and acylcarnitine content is increased in mitochondria isolated from an ischaemic area of the myocardium. In analysing the FA derivative content, we discovered that long-chain acylcarnitines, but not acyl-CoAs, accumulate at concentrations that are harmful to mitochondria. Acylcarnitine accumulation in the mitochondrial intermembrane space is a result of increased carnitine palmitoyltransferase 1 (CPT1) and decreased carnitine palmitoyltransferase 2 (CPT2) activity in ischaemic myocardium and it leads to inhibition of oxidative phosphorylation, which in turn induces mitochondrial membrane hyperpolarization and stimulates the production of reactive oxygen species (ROS) in cardiac mitochondria. Thanks to protection mediated by acyl-CoA-binding protein (ACBP), the heart is much better guarded against the damaging effects of acyl-CoAs than against acylcarnitines. Supplementation of perfusion buffer with palmitoylcarnitine (PC) before occlusion resulted in a 2-fold increase in the acylcarnitine content of the heart and increased the infarct size (IS) by 33%. A pharmacologically induced decrease in the mitochondrial acylcarnitine content reduced the IS by 44%. Long-chain acylcarnitines are harmful FA intermediates, accumulating in ischaemic heart mitochondria and inducing inhibition of oxidative phosphorylation. Therefore, decreasing the acylcarnitine content via cardioprotective drugs may represent a novel treatment strategy.
科研通智能强力驱动
Strongly Powered by AbleSci AI