Search

[Display omitted] • • ERα decline in the postmenopausal stage increases TLR4 activation in macrophages to promote plaque instability. • • Estrogen or phytoestrogen therapy reduces macrophage-associated inflammation and matrix degradation to improve plaque instability. • • ERα mediated the regulation of estrogen and phytoestrogens on macrophages by inhibiting TLR4 signal activation. Acute cardiovascular events increase significantly in postmenopausal women. The relationship between estrogen receptor (ER) and plaque stability in the postmenopausal stage remains to be elucidated. We aimed to explore whether ERα activation improves plaque instability in the postmenopausal stage. Here, we report that postmenopausal women showed increased macrophage activation and plaque instability with increased MCP-1, MMP9, TLR4, MYD88 and NF-κB p65 and decreased ERα and TIMP1 expression in the vascular endothelium. Moreover, ovariectomy in LDLR-/- mice resulted in a significant increase in plaque area and necrotic core area, as well as a significant decrease in collagen content and an increase in macrophage accumulation in the artery. Ovariectomy also reduced serum estrogen levels and ERα expression and upregulated TLR4 and MMP9 expression in arteries in LDLR-/- mice. Estrogen or phytoestrogen therapy upregulated the expression level of ERα in ovariectomized mice and increased plaque stability by inhibiting macrophage accumulation and TLR4 signaling. In vitro, LPS incubation of RAW264.7 cells resulted in a significant decrease in ERα and TIMP1 expression and an increase in TLR4 activation, and estrogen or phytoestrogen treatment increased ERα and TIMP1 expression and inhibited TLR4 activation and MMP9 expression in LPS-treated RAW264.7 cells. Compared to control siRNA transfected RAW264.7 cells, TLR4 siRNA promoted TIMP1 expression in RAW264.7 cells with LPS incubation, but did not affect ERα expression in RAW264.7 cells with or without LPS treatment. The ERα inhibitor MPP abolished the regulatory effect of estrogen or phytoestrogen on LPS-induced RAW264.7 cells. In conclusion, the present study demonstrates that decreased ERα expression promotes macrophage infiltration and plaque instability in the postmenopausal stage, and activation of ERα in the postmenopausal stage alleviates atherosclerotic plaque instability by inhibiting TLR4 signaling and macrophage-related inflammation. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is one of the most common causes of cardiovascular diseases in the world. Currently, the drugs used to treat HF in the clinic may cause serious side effects. Liguzinediol, 2, 5-dimethyl-3, 6-dimethyl-pyrazine, is a compound synthesized after the structural modification of ligustrazine (one active ingredient of Szechwan Lovage Rhizome). We aimed to observe the effects of liguzinediol on preventing HF and explore the related mechanisms. Methods: The ligation of left anterior descending coronary artery was operated to established the myocardial infarction (MI) model in Sprague–Dawley rats. Cardiac functions were recorded by echocardiography and hemodynamics. The changes in the Renin–Angiotensin–Aldosterone System (RAAS), inflammation, and oxidative stress were detected by radioimmunoassay and Elisa kits. Western blot and real-time PCR were applied to determine the expressions of the TGF-β1/Smads pathway. Results: Firstly, liguzinediol enhanced the systolic and diastolic functions of the heart in MI rats. Liguzinediol improved ventricular remodeling by reducing myocardial cell necrosis, as well as reducing collagen deposition and myocardial fibrosis. Then, liguzinediol suppressed the activation of RAAS, inhibited the synthesis of pro-inflammation factors, and reduced oxidative stress. In the end, liguzinediol also down-regulated the expressions of the TGF-β1/Smads pathway. Conclusions: Liguzinediol could alleviate HF caused by MI in rats, and the protective effect was associated with the regulation of the TGF-β1/Smads pathway. [ABSTRACT FROM AUTHOR]

Background: The long-term excessive intake of exogenous cholesterol can lead to abnormally elevated blood lipid levels and induce cardiovascular and cerebrovascular diseases. However, the influence and relevance of exogenous cholesterol on plasma cholesterol components were still unclear, and the influence on intestinal lipid metabolism targets needs to be further explored. Methods: In vivo, the C57BL/6 + NF group and ApoE−/− + NF group mice were fed a normal specific pathogen-free (SPF) diet; the ApoE−/− + HF group mice were fed a high-cholesterol SPF diet. The plasma and jejunum tissue homogenate were obtained for non-targeted lipid metabolomics. The lipid droplets in tissues were observed by transmission electron microscope and oil red O staining. Jejunum tissue morphology was observed by HE staining. The kits were used to detect lipid content in plasma, tissues, intestinal contents, and cells. Western blot, RT-PCR, immunohistochemistry (IHC), and immunofluorescence (IF) were used to observe the key target of lipid metabolism. In vitro, the final concentration of cholesterol was 100 μmol/L in Caco-cells. Oil red O staining, western blot, RT-PCR and immunofluorescence (IF) were used to observe the changes of lipid metabolism. Finally, the influence of liver X receptor alpha (LXRα) on intestinal cholesterol metabolism was clarified by applying the LXRα inhibitor GSK2033 and siRNA targeting LXRα. Results: The aortic arch and intestinal villi of the two groups of ApoE−/− mice showed apparent lesions and lipid accumulation, and there were significant changes in a variety of lipids in the plasma and jejunum. Additionally, jejunum LXRα was markedly activated. High cholesterol can significantly activate LXRα in Caco-2 cells. After LXRα was inhibited, the protein level of ATP-binding cassette transporter A1/G5/G8 (ABCA1/G5/G8) decreased, and the quantity and volume of intracellular lipids soared. Conclusion: In a high-cholesterol environment, the intestine promotes the excretion of cholesterol from the cell through the LXRα-ABCA1/G5/G8 pathway, reduces the intestinal intake of a variety of exogenous cholesterol, and reduces the risk of AS. [ABSTRACT FROM AUTHOR]

The risk of atherosclerosis (AS) ascends among post-menopausal women, while current hormone replacement therapy exerts several adverse effects. Alisol B 23-acetate (AB23A), a tetracyclic triterpenoid isolated from the rhizome of Alisma orientale , was reported to show multiple physiological activities, including regulating lipid metabolism. According to molecular docking analysis, it was predicted to bind with estrogen receptor α (ERα). In this study, we aimed to observe the effect of AB23A on preventing post-menopausal AS and explore whether the mechanism was mediated by ERα. In vitro, free fatty acid (FFA) was applied to induce the abnormal lipid metabolism of L02 cells. In vivo, the ApoE−/− mice were ovariectomized to mimic the cessation of estrogen. The high-fat diet was also given to induce post-menopausal AS. We demonstrated AB23A attenuated the accumulation of total cholesterol and triglyceride induced by free fatty acids in hepatocytes. In high-fat diet-ovariectomy-treated ApoE−/− mice, AB23A eliminated lipids in blood and liver. AB23A not only reduced the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) through sterol-regulatory element binding proteins (SREBPs) but also suppressed the secretion of PCSK9 through silent information regulator 1 (SIRT1). Notably, AB23A promoted the expression of ERα in vivo and in vitro. The both ERα inhibitor and ERα siRNA were also applied in confirming whether the hepatic protective effect of AB23A was mediated by ERα. We found that AB23A significantly promoted the expression of ERα. AB23A could inhibit the synthesis and secretion of PCSK9 through ERα, lower the accumulation of triglyceride and cholesterol, and prevent post-menopausal AS. Unlabelled Image [ABSTRACT FROM AUTHOR]

Decreases in estrogen secretion and estrogen receptor function lead to an increase in the incidence of dyslipidemia and cardiovascular disease (CVD) in postmenopausal women. We previously reported that β-estradiol has a significant regulatory effect on lipids in ApoE−/− mice with bilateral ovariectomy. In the present study, we investigated how β-estradiol regulates intestinal function via estrogen receptors to alleviate postmenopausal dyslipidemia. Ovariectomized ApoE−/− mice were treated with β-estradiol for 90 days, and we found that β-estradiol reduced TC, TG, LDL-c, IL-1β and IL-18 levels in serum and decreased lipid accumulation in the liver. β-estradiol reduced injury and inflammation in the jejunum in ovariectomized mice, and promoted the expression of tight junction-related proteins. Moreover, β-estradiol increased ERα, ERβ, GPR30 and ABCG5 protein expression, and decreased the levels of NPC1L1 and SR-B1 in the jejunum of ovariectomized mice. In Caco-2 cells incubated with cholesterol, β-estradiol up-regulated PI3K/AKT signaling, reduced cholesterol accumulation, suppressed inflammatory signaling, and increased the expression of tight junction-related proteins. ERβ or GPR30 inhibition decreased the protective effect of β-estradiol on cholesterol accumulation, tight junctions, and inflammation in cholesterol incubated Caco-2 cells, while silencing both ERβ and GPR30 completely eliminated the protective effect of β-estradiol. PI3K/AKT inhibition abolished the protective effect of β-estradiol on cholesterol accumulation, tight junction-related protein expression, and inflammation, but had no influence on ERα, ERβ or GPR30 expression in cholesterol incubated Caco-2 cells. Our results provide evidence that β-estradiol regulates intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia. [ABSTRACT FROM AUTHOR]