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.