Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart: New anti-angina mechanism implication
Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart: New anti-angina mechanism implication
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原儿茶酸代谢影响大鼠心脏脂肪酸氧化：新的抗心绞痛机制意义
DOI：
10.1016/j.bcp.2008.11.029
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发表时间：
2009-03-15
影响因子：
5.8
通讯作者：
Liu, Xiao-quan
中科院分区：
文献类型：
--
作者：
Cao, Yan-guang;Zhang, Lin;Liu, Xiao-quan
原儿茶酸（PA）是丹参中一种结构典型的酚酸，具有抗心绞痛作用。但迄今为止，除了清除氧自由基外，对其抗心绞痛机制的认识还很有限。本研究基于PA在大鼠心脏中的新代谢途径及其对脂肪酸氧化（FAO）的影响，提出了PA抗心绞痛的新机制。详细地，在大鼠心脏中鉴定了三种代谢物，即儿茶酚甲基化代谢物、酰基辅酶（CoA）硫酯和甘氨酸缀合物。基于与心脏线粒体、细胞质、微粒体和匀浆孵育的几种代谢系统，证实了一种新的代谢途径。结果表明，PA首先在微粒体和胞液中发生甲基化反应，这是PA进一步代谢的先决条件，并能被托卡朋抑制，然后甲基化代谢产物香草酸扩散到线粒体中，在线粒体中转化为酰基CoA硫酯，与FAO相似。此外，部分酰基辅酶A硫酯转化为甘氨酸结合，这一步骤也位于线粒体内。在离体大鼠心脏灌流实验中，PA可显著降低FAO，表现为灌流液中残余脂肪酸含量增加（p < 0.05），心脏中酰基辅酶A/辅酶A比值降低（p < 0.05）。PA对FAO的抑制作用可被其甲基化抑制剂托卡朋逆转，表明该作用与PA在心脏中的代谢途径密切相关。FAO的减少可能使心脏能量底物偏好从脂肪酸转向葡萄糖，这对缺血心脏是有利的。(C)2008年爱思唯尔公司All rights reserved.
Protocatechuic acid (PA), a structurally typical phenolic acid in danshen, shows anti-angina efficacy. But until now, besides scavenging of oxygen free radicals, the understanding of its anti-angina mechanism has been limited. In our study, based on a novel metabolic route of PA identified in rat heart and its influence on fatty acid oxidation (FAO), we proposed a new mechanism for its anti-angina. in detail, three metabolites, catechol methylated metabolite, acyl-coenzyme (CoA) thioester and glycine conjugation, were identified in rat heart. A novel metabolic pathway was confirmed based on several metabolic systems incubated with heart mitochondria, cytosol, microsomes and homogenate. Results indicated that PA was firstly methylated in microsomes and cytosol, which was regarded as the prerequisite step for further metabolism and could be inhibited by tolcapone, and then the resulting methylated metabolite (vanillic acid) diffused into mitochondria where it was converted into acyl-CoA thioester, in similar with FAO. In addition, part of the acyl-CoA thioester was transformed into glycine conjugation, a step also localized within mitochondria. Furthermore, based on isolated rat heart perfusion, it was found that PA markedly decreased FAO, which was shown by higher residual fatty acid level in perfusate (p < 0.05) and lower acy-CoA/CoA ratio in heart (p < 0.05). The FAO inhibiting effect of PA could be largely reversed by its methylation inhibitor tolcapone, indicating the effect was closely related with the identified metabolic pathway of PA in heart. The decrease of FAO may switch heart energy substrate preference from fatty acid to glucose, which is beneficial for ischemia heart. (C) 2008 Elsevier Inc. All rights reserved.