Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy

Abstract

The failing heart is characterized by an increase in glucose uptake and glycolytic rates that is not accompanied by a concomitant increase in glucose oxidation. Lower coupling of glucose oxidation to glycolysis possibly owes to unchanged or reduced pyruvate oxidation in mitochondria. Therefore, increasing pyruvate oxidation may lead to new therapies for heart disease. Dihydrolipoamide dehydrogenase (DLD) is a component of the pyruvate dehydrogenase complex (PDH). DLD mutations or defects are closely associated with metabolic diseases. However, few studies explore the effects of DLD mutants or acylation status on PDH activity and pyruvate metabolism. P300 is protein 2-hydroxyisobutyryltransferases in cells, and P300-dependent lysine 2-hydroxyisobutyrylation of glycolytic enzymes affects glucose metabolism. However, there are no relevant reports on the effect of 2-hydroxyisobutyrylation on the energy metabolism of heart failure, and it is worth further in-depth study. In this study, we showed that 2-hydroxyisobutyrylation is an essential protein translational modification (PTM) that regulates the activity of pyruvate dehydrogenase complex (PDHc). In a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy, the 2-hydroxyisobutylation of DLD was significantly increased, related to the decrease in PDH activity. In addition, our data provide clear evidence that DLD is a direct substrate of P300. As one of the main active ingredients of ginseng, ginsenoside Rg3 (Rg3) can reduce the 2-hydroxyisobutylation levels of DLD and restore the PDH activity by inhibiting the acyltransferase activity of P300, thereby producing beneficial effects whenever the heart is injured. Therefore, this study suggests a novel strategy for reversing myocardial hypertrophy.

Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling

“…Ginsenosides and their isomers, which comprise around 25% of the total GYPs in G. pentaphyllum , also have strong potency in treating HF ( Lu et al, 2023 ). Under stress conditions, ginsenosides Rb1 ( Li et al, 2017 ), Rb3 ( Chen et al, 2019 ), Rg1 ( Dong et al, 2016 ; Liu et al, 2022 ), Rg3 ( Ni et al, 2022 ), and Rd ( Wang et al, 2013b ) can regulate mitochondrial pathway networks, thus preserving mitochondrial homeostasis and heart function. Better understanding of the mechanisms of GYPs in governing mitochondrial homeostasis will facilitate their development as cardiovascular medications.…”

The protective role of ginsenoside Rg3 in heart diseases and mental disorders

“…In HF, the 2-hydroxyisobutylation of DLD was significantly upregulated, resulting from the downregulation of PDHc activity. However, Rg3 can lower the 2-hydroxyisobutylation levels of DLD and maintain the PDHc activity by suppressing the acyltransferase activity of P300, further regulating pyruvate metabolism and sustaining glucose homeostasis in cardiac tissue, consequently, improving cardiac function ( Ni et al, 2022b ).…”