[Fuyu Decoction ameliorates myocardial fibrosis in rat model of heart failure by regulating Nrf2/GPX4-mediated ferroptosis].

This study aims to investigate the effect and mechanism of Fuyu Decoction(FYD) in the treatment of myocardial fibrosis in the rat model of heart failure(HF). Sixty Wistar rats were randomized into a modeling group(n=50) and a sham group(n=10). A post-myocardial infarction HF model was established by ligating the left anterior descending coronary artery in rats. The successfully modeled rats were assigned into model, low-dose(2.5 g·kg~(-1)) FYD(FYD-L), high-dose(5.0 g·kg~(-1)) FYD(FYD-H), and FYD+Nrf2 inhibitor(ML385, 30 mg·kg~(-1)) groups(n=10). FYD was administrated by gavage and ML385 by intraperitoneal injection. The rats in the sham and model groups were administrated with equal amounts of normal saline by gavage. After 8 weeks of intervention, the cardiac function indicators were measured, and the myocardial tissue morphology and collagen deposition were observed. The positive expression of collagens Ⅰ and Ⅲ, apoptosis, and oxidative stress were examined, and the levels of Fe~(2+) and reactive oxygen species(ROS) were determined. The protein levels of nuclear factor erythroid 2-related factor 2(Nrf2), solute carrier family 7 member 11(SLC7A11), glutathione peroxidase 4(GPX4), and acyl-coenzyme A synthase long chain family member 4(ACSL4) in the myocardial tissue were determined. Compared with sham group, the model group showed decreased left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), increased left ventricular end internal dimension in systole(LVIDs), left ventricular internal diameter in diastole(LVIDd), and myocardial collagen deposition, positive expression of collagens Ⅰ and Ⅲ, elevated apoptosis rate and malondialdehyde(MDA), Fe~(2+), and ROS levels, lowered superoxide dismutase(SOD) and glutathione peroxidase(GSH) levels, down-regulated protein levels of Nrf2, SLC7A11, and GPX4, and up-regulated protein level of ACSL4. Compared with the model group, the above indicators were restored by FYD. Moreover, ML385 reversed the protective effect of FYD on myocardial fibrosis in HF rats. In conclusion, FYD can inhibit ferroptosis by activating the Nrf2/GPX4 pathway, thereby ameliorating myocardial fibrosis in HF rats.

[Yinxingye Capsule Intervened Vascular Endothelial Cell Apoptosis of Hyperhomocysteinemia Rats: an Experimental Study].

OBJECTIVE: To explore targets of Chinese herbal medicine at cellular and molecular leve1s through an experimental study on Yinxingye Capsule (YC) intervening vascular endothelial cell apoptoeis of hyperhornocysteinemia (HHcy) rats. METHODS: The HHcy model was prepared in male Wistar rats. Totally 42 rats were randomly divided into 4 groups, i.e., the control group (n =10), the model group (n = 11), the YC group (n =11), the folic acid group (n =10). Carboxy methyl cellulose (CMC) solution (1%) was administered to rats in the control group by gastrogavage.3% methionine suspension at 1. 5 g/kg was administered to rats in the model group by gastrogavage. 3% methionine suspension at 1. 5 g/kg and folic acid suspension at 0. 06 g/kg was administered to rats in the folic acid group by gastrogavage. 3% methionine suspension at 1. 5 g/kg and YC at 0. 02 g/kg was administered to rats in the YC group by gastrogavage. Morphological changes of aortic tissue were observed by hematoxylin eosin (HE) staining. The plasma homocysteine (Hcy) level was detected in each group. The endothelium-dependent diastolic functions of the thoracic aorta on different concentrations of sodium nitroprusside (SNP) and acetylcholine (Ach) were detected. Gene expressions of Bcl-2-associated X protein (BAX), inducible nitric oxide synthase (iNOS), c-Fos, cellular inhibitor of apoptosis protein 2 (c-IAP2) were detected by real time polymerase chain reaction (RT-PCR). RESULTS: Pathological results showed that thickening aortic endothelium, swollen and desquamated endothelial cells. Few foam cells could be seen in the model group. Myoma-like proliferation of smooth muscle cells in tunica media could also be seen. These pathological changes were milder in the YC group and the folic acid group. Compared with the control group, plasma Hcy levels increased in the model group (P <0. 05). The endothelium-dependent diastolic rates at 10(-6) and 10(-4)mol/L Ach and 10(-7) -10(-3)mol/L SNP all decreased in the model group (P <0. 01, P <0. 05). Gene expressions of Bax, c-Fos, and iNOS increased, but c-IAP2 gene expressions decreased in the model group (all P <0. 05). Compared with the model group, plasma Hcy levels decreased in the YC group and the folic acid group (P <0. 05). The endothelium-dependent diastolic rates increased in the YC group and the folic acid group at various SNP concentrations except 10(-6) mol/L SNP in the folic acid group. The endothelium-dependent diastolic rates increased in the YC group and the folic acid group at 10(-6) and 10(-4)mol/L Ach (all P <0. 05). Gene expressions of Bax, c-Fos, and iNOS decreased in the YC group and the folic acid group, but c-IAP2 gene expression increased in the folic acid group (all P <0. 05). CONCLUSION: YC could reduce plasma Hcy levels, down-regulate gene expressions of Bax, c-Fos, and iNOS, thereby reducing apoptosis of vascular endothelial cells, improving vascular endothelial function, and delaying atherosclerotic process.