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Astragaloside IV alleviates heart failure via activating PPAR? to switch glycolysis to fatty acid ?-oxidation.

ABSTRACT: In heart failure (HF), energy metabolism pathway in cardiac muscle changes from fatty acid ?-oxidation to glycolysis. However, the exact mechanism is unknown. Sarcoendoplasmic reticulum Ca²⁺? 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 ?-oxidation rate. We investigated whether Astragaloside IV can activate peroxisome proliferator-activated receptor alpha (PPAR?) to stimulate fatty acid ?-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 ?-oxidation and heart function were substantially strengthened following Astragaloside IV treatment, as demonstrated by the increased expression of PPAR? 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 ?-oxidation, as confirmed by reduced anaerobic glycolysis and an increased oxygen consumption ratio. These results suggest that Astragaloside IV can stimulate fatty acid ?-oxidation and improve mitochondrial function, which may present a novel cardioprotective treatment that inhibits the progress of HF.

SUBMITTER: Dong Z

PROVIDER: S-EPMC5457407 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Astragaloside IV alleviates heart failure via activating PPARα to switch glycolysis to fatty acid β-oxidation.

Dong Zhiwei Z Zhao Pei P Xu Ming M Zhang Chen C Guo Wei W Chen Huihua H Tian Jing J Wei Hongchang H Lu Rong R Cao Tongtong T

Scientific reports 20170602 1

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 Ca<sup>2+</sup>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 peroxis ...[more]

PMID: 28578382

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Project description:The present study investigated whether the protective effect and mechanism of astragaloside IV (AS-IV) on heart failure (HF) involves small ubiquitin-like modifier (SUMO)-specific protease 1 (Senp1). Mouse HF was established by aortic constriction, inducing pressure overload. The model was confirmed by echocardiography 6 weeks after surgery. Mice were randomly divided into control, HF, HF+AS-IV, and AS-IV groups. Ventricular function was examined by echocardiography. Morphological changes of myocardial tissues were examined by H&E staining. The protein levels of the apoptosis-related proteins, cleaved caspase-3, caspase-3, Bcl2, Bax, and SUMO-Senp1 were determined by Western blotting. H2O2 in isolated mitochondria and cells was determined by Amplex Red. A reactive oxygen species (ROS) detection kit determined ROS levels in isolated mitochondria and HL-1 cells. JC-1 reagent measured mitochondrial membrane potential (ΔΨm). Apoptosis of HL-1 cells was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling. Compared with the control group, the heart weight and heart mass/body weight ratio increased in the HF group (P<0.05). Furthermore, the ejection fraction and left ventricular shortening fraction decreased (P<0.05), while the left ventricular end-diastolic diameter (LVID;d) and end-systolic diameter (LVID;s) increased (P<0.05). Finally, mitochondrial ROS and H2O2 increased (P<0.05), while the ΔΨm decreased (P<0.05). However, AS-IV improved the cardiac function of HF mice, decreased the level of ROS and H2O2 in the myocardium, suppressed the decrease in ΔΨm, and decreased the apoptosis of myocardial cells (P<0.05). AS-IV also decreased the Senp1-overexpression. Furthermore, in HL-1 cells, Senp1-overexpression significantly inhibited the protective effects of AS-IV. AS-IV decreased oxidative stress in cardiomyocytes, decreased mitochondrial damage, inhibited ventricular remodeling, and ultimately improved cardiac function by inhibiting HF-induced Senp1-overexpression. This mechanism provides a novel theoretical basis and clinical treatment for HF.

Dataset Information

Astragaloside IV alleviates heart failure via activating PPAR? to switch glycolysis to fatty acid ?-oxidation.

Publications

Astragaloside IV alleviates heart failure via activating PPARα to switch glycolysis to fatty acid β-oxidation.

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