Salvianolic acid B drives gluconeogenesis and peroxisomal redox remodeling in cardiac ischemia/reperfusion injury: A metabolism regulation by metabolite signal crosstalk.

Abstract

Cardiac metabolism relies on glycogen conversion by glycolysis. Glycolysis intersects fatty acid oxidation and often directs a signal crosstalk between redox metabolites. Myocardium with ischemia/reperfusion significantly diverts from normal metabolism. Prospectively, peroxisome lies central to metabolism and redox changes, but mechanisms underlying in ischemia/reperfusion remain undefined. This work aims at investigating the potential effects and mechanisms of Salvianolic acid B (Sal B) in cardioprotection through metabolic remodeling. Following experiments, we found that Sal B is absorbed in blood and rat hearts and its cardiac absorption prevents ischemia/reperfusion injury. Sal B cardioprotection relates to gluconeogenesis activation and peroxisomal redox remodeling. Gluconeogenesis compensates glycogen synthesis through upregulating pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase. Gluconeogenic PC activity drives peroxisomal Pex2/Pex3 expressions and promotes the proliferation of peroxisome. Peroxisome quality control is enhanced with Pex5/Pex14/Pex13/Pex2 transcriptions. Nono, a non-POU domain-containing octamer-binding protein, promotes upregulation of gluconeogenic PC and peroxisomal gene transcripts through transcriptionally splicing their pre-RNAs at octamer duplex. Nono also controls the expression of SARM1/PARP1/sirtuin1 for catalyzing nicotinamide adenine dinucleotide (NAD⁺) consumption, leading to endurable redox capacities of peroxisome. Peroxisomal redox remodeling alters reactive oxygen species (ROS) and NAD⁺ contents, following which NAD⁺ affects cardiac accumulation of physiologically harmful glucocorticoid. In the tests of Sal B combinational treatments, results indicate ROS upregulation whereas NAD⁺ downregulation with glucocorticoid, ROS scavenging and glucocorticoid elimination with NAD⁺ precursor, and NAD⁺ promotion with ROS scavenger, respectively. This metabolite signal crosstalk alternatively antagonizes/agonizes Sal B cardioprotective functions on electrocardiographic output and infarction. Taken together, we reported a cardiac metabolism regulation with Sal B, capable of preventing myocardium from ischemia/reperfusion injury. The metabolite signal crosstalk was achieved by coupling reaction cascades between gluconeogenesis and peroxisomal redox remodeling.