In vivo gum arabic-coated tetrahydrobiopterin protects against myocardial ischemia reperfusion injury by preserving eNOS coupling

Abstract

AimsExogenous tetrahydrobiopterin (BH4), an indispensable cofactor of endothelial nitric oxide synthase (eNOS), supplementation has been proved to be of advantage to improve cardiovascular function. Nevertheless, due to its highly redox-sensitive and easy to be oxidized, there is an urgent need to develop an appropriate BH4 formulation for clinical therapy. Gum Arabic (GA) has been considered as an alternative biopolymer for the stabilization and coating of drugs. The effects of GA on protecting BH4 from being oxidized were investigated in a rat model of myocardial ischemia-reperfusion (I/R). Main methodsRats were subjected to 60-min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic GA-coated BH4 supplementation (10 mg/kg, oral). Myocardial infarction, fibrotic area and left ventricle ejection fraction were correlated with cardiac BH4 content, eNOS protein, NOS enzyme activity, and ROS/NO generation. Key findingsPretreatment of rats with GA-coated 6R-BH4, 24 h before myocardial ischemia, resulted in smaller myocardial infarction, improved left ventricular function and inhibited fibrosis, correlated with maintained high levels of cardiac BH4 content, preserved eNOS activation and dimerization, and decreased ROS generation. However in uncoated group, 6R-BH4 treatment did not reduce acute and chronic myocardial I/R injury compared with control I/R rats, which was closely related with the marked loss of myocardial BH4 levels during I/R. SignificanceThese findings provide evidence that in vivo pre-ischemic oral GA-coated BH4 administration preserves eNOS function secondary to maintaining cardiac BH4 content, and confers cardioprotection after I/R.