Abstract
In heart failure (HF), energy metabolism pathway in cardiac muscle changes from fatty acid β-oxidation to glycolysis. However, the exact mechanism is unknown. Sarcoendoplasmic reticulum Ca2+α ATPase (SERCA) expression is downregulated and mitochondrial function is reduced in HF, perhaps partly due to a substantially reduced energy supply for excitation–contraction coupling resulting from a lower fatty acid β-oxidation rate. We investigated whether Astragaloside IV can activate peroxisome proliferator-activated receptor alpha (PPARα) to stimulate fatty acid β-oxidation and increase cardiac energy production, improving mitochondrial function and the efficiency of SERCA in HF. In pressure overload-induced HF mice and isolated hypertrophic myocardial cells, fatty acid β-oxidation and heart function were substantially strengthened following Astragaloside IV treatment, as demonstrated by the increased expression of PPARα and SERCA2a. In vitro, Astragaloside IV regulated energy metabolism by increasing ATP production and enhancing mitochondrial function, attributable to increased oxygen consumption and slightly increased mitochondrial Ca2+ uptake. In HF, Astragaloside IV switched glycolysis to fatty acid β-oxidation, as confirmed by reduced anaerobic glycolysis and an increased oxygen consumption ratio. These results suggest that Astragaloside IV can stimulate fatty acid β-oxidation and improve mitochondrial function, which may present a novel cardioprotective treatment that inhibits the progress of HF.
Highlights
During the fetal period, glycolysis is the chief energy metabolism pathway in cardiac muscle cells, switching to fatty acid β-oxidation after birth
To investigate the potential protective effects of Astragaloside IV (AST) in heart failure (HF), we conducted a study with a mouse model of HF induced by transverse aortic constriction (TAC)
AST and GW7647 treatment both showed a higher Ca2+ uptake rate than that of the TAC group. These results suggest that AST has an effect in promoting mitochondrial function by regulating calcium uptake, mitochondrial basal calcium, membrane potential and permeability transition pore opening, confirming that PPARα activation could be a key target for AST in this process
Summary
Glycolysis is the chief energy metabolism pathway in cardiac muscle cells, switching to fatty acid β-oxidation after birth. Mitochondrial biological function plays a vital role in energy production and cellular metabolic functions[15, 16], and there has been considerable study of the key role played by mitochondrial Ca2+ uptake in increasing ATP synthesis and stimulating Krebs cycle activity, as well as its involvement in the HF progression[17, 18]. It has been shown to have multiple beneficial effects on diabetes through promoting the expression of PPARγ22, 23, and it has recently been shown to have a therapeutic action in neurodegenerative disease[24] It exhibits substantial inhibitory effect on apoptosis and the oxidative stress on hypertrophic cardiomyocytes in vivo and in vitro[25]. We tested the hypothesis that AST would have beneficial effects on HF via stimulating PPARα expression and promoting mitochondrial metabolism to meet the energy consumption of normal excitation–contraction coupling
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