Search

Angiopoietin Like protein 3 (ANGPTL3) is at present considered as a central molecular target for therapy designed to reduce atherogenic lipids and atherosclerosis. However, concerns about the safety of inactivation of ANGPTL3 in patients with coronary artery disease (CAD) especially myocardial infarction (MI) have been raised. ANGPTL3 is reported to possess proangiogenic property. Angiogenesis is critical to the recovery of MI. Endothelial progenitor cells (EPCs) have multiple differentiation potential and play an important role in the angiogenesis post-MI. Promoting the function of EPCs could facilitate the angiogenesis and recovery of MI. Previous studies have shown that ANGPTL3 can promote angiogenesis in corneal of rats and promote angiogenesis of endothelial cells by binding to integrin ανβ3 receptors and promoting phosphorylation of protein kinase B (AKT). Our institution found that activated AKT can up-regulate the expression of microRNA-126 (miR-126), which can promote the proangiogenic ability of EPCs. The integrin ανβ3 receptors and AKT also express in EPCs and are closely related to proangiogenic function. Therefore, we hypothesized that ANGPTL3 could improve function of EPCs by binding to integrin ανβ3 receptors and up-regulating miR-126 expression via activating AKT, thus promoting the formation of new blood vessels, attenuating myocardial ischemia and improving heart function.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and it has been confirmed that increased low density lipoprotein cholesterol (LDL-C) is an independent risk factor for atherosclerosis. Recently, the increasing evidence has showed that hypertriglyceridemia is associated with incremental ASCVD risk. But the proatherogenic mechanism of triglyceride (TG) remains unclear. Therefore, this article focuses on the clinical studies and proatherogenic mechanism related to hypertriglyceridemia, in order to provide reference for the prevention and treatment of ASCVD.

Background Estrogen was reported to protect against obesity, however the mechanism remains unclear. We aimed to investigate the impact of 17β-estradiol (17β-E2) on triglyceride metabolism in adipocytes with or without lipopolysacchride (LPS) stimulating, providing novel potential mechanism for estrogen action. Methods 3T3-L1 adipocytes were cultured and differentiated into mature adipocytes in vitro. The differentiated 3T3-L1 cells were divided into six groups: (i) control group, treated with 0.1% DMSO alone; (ii) 17β-E2 group, treated with 1, 0.1, or 0.001 μM 17β-E2 for 48 h; (iii) 17β-E2 plus MPP group, pre-treated with 10 μM MPP (a selective ERα receptor inhibitor) for 1 h, then incubated with 1 μM 17β-E2 for 48 h; (iv) 17β-E2 plus PHTPP group, pre-treated with 10 μM PHTPP (a selective ERβ receptor inhibitor), then incubated with 1 μM 17β-E2 for 48 h; (v) LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 0.1% DMSO alone for 48 h; (vi) 17β-E2 plus LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 1 μM 17β-E2 for 48 h. The levels of triglyceride and adipose triglyceride lipase (ATGL) in differentiated 3T3-L1 cells and the concentrations of interleukin-6 (IL-6) in culture medium were measured. Results Comparing with control group, 1 μM and 0.1 μM 17β-E2 decreased the intracellular TG levels by about 20% and 10% respectively (all P 0.05). There was no significant difference in the triglyceride contents of differentiated 3T3-L1 cells among control group, LPS group and 17β-E2 + LPS group (all P > 0.05). ATGL expression in 17β-E2 group was significantly higher than control group (P

Estrogen had been found to be negatively associated with serum triglyceride (TG) levels. Apolipoprotein A5 (APOA5), a novel member of apolipoprotein family, was reported to have a strong ability to decrease serum concentrations of TG. Clinical data found concentrations of APOA5 were higher in woman than that in men, and the negative relationship between APOA5 and TG levels was more significant in woman. These suggests APOA5 may involve in estrogen actions. Therefore, we hypothesize estrogen up-regulates serum concentrations of APOA5 and subsequently decreases serum TG levels. We will design the following experiments to test this hypothesis. (1) We will treat wild and APOA5-defeted ovariectomized hamster with or without estrogen to examine if estrogen could up-regulate concentrations of APOA5 and decrease TG levels. (2) We will treat HepG2 cells with estrogen and investigate the possible mechanisms.

Metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D). Recently, several studies have confirmed that metformin possessed multiple cardiovascular protective effects such as decreasing cardiovascular mortality, attenuating adverse cardiac and vascular remodeling and ameliorating atherosclerosis [1–3]. Hong et al. [4] in a multicenter, randomized, double-blind, placebo-controlled clinical trial found treatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide in type 2 diabetes patients who had a history of coronary artery disease. Forouzandeh et al. [5] demonstrated metformin treatment significantly attenuated high-fat diet-induced atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. These studies suggest metformin could ameliorate atherosclerosis, but the anti-atherosclerotic mechanism of metformin remains to be fully clarified. Previous studies reported that metformin could decrease plasma cholesterol levels in diabetic and non-diabetic patients beyond its glucose-lowering effect [6–9], and the lipid-lowering effect of metformin was also confirmed in a meta-analysis of randomized controlled trials (RCTs) [10]. Besides, it was found that metformin treatment could lower inflammation markers levels in patients at high risk of cardiovascular disease and restore impaired HDL-mediated cholesterol efflux from macrophages due to glycation [11, 12]. These effects may contribute to the anti-atherosclerotic properties of metformin. The deposition of excessive cholesterol in macrophages plays a key role in atherosclerotic plaque formation, thus removal of excess cholesterol from macrophages may attenuate and even regress the atherosclerosis [13]. It has been identified that removal of cholesterol from macrophages was mediated by several transmembrane transporters, including adenosine triphosphate binding cassette (ABC) transporters A1 and G1 [14]. Yvan-Charvet et al. [15] evidenced that combined deficiency of Abca1 and Abcg1 in macrophages severely damaged cholesterol efflux and accelerated atherosclerosis in low-density lipoprotein receptor-knockout (Ldlr-/-) mice. Bochem et al. [16] demonstrated that carriers of ABCA1 loss-of-function mutations presented with lower cholesterol efflux capacity and higher atherosclerotic burden compared with age and sex-matched controls. Conversely, increased expression of ABCA1 and ABCG1 was involved in redistribution of cholesterol from inner to outer leaflet of the plasma membrane, facilitating cholesterol efflux from cholesterol-loaded macrophages [17]. Overexpression of ABCA1 in macrophages increased cholesterol efflux by about 60 % (P = 0.0006) and reduced atherosclerotic plaques by about 68 % (P = 0.0008) in Ldlr-/- mice fed a Western-type diet for 12 weeks [18]. Thus, ABCA1- and ABCG1-driven cholesterol efflux in macrophages was a key regulator in anti-atherosclerosis. Fibroblast growth factor (FGF) 21, a member of FGF subfamily and mainly secreted by liver and adipose tissue, is a novel metabolic regulator with multiple cardioprotective efficacy [19]. It was found that FGF21 deficiency caused a marked exacerbation of atherosclerotic plaque formation in ApoE−/− mice [20]. Moreover, previous studies also demonstrated that FGF21 could activate ABCA1 and ABCG1 expression of macrophages and in turn promoted cholesterol efflux in macrophages [21, 22], suggesting up-regulation of FGF21 exerted function of reducing atherosclerotic plaques. Intriguingly, Nygaard et al. [23] found metformin significantly increased FGF21 expression in both rat and human hepatocytes. Another study showed metformin could increase serum FGF21 levels both in mice and human [24]. Thus, we speculate metformin stimulates ABCA1 and ABCG1 expression via up-regulation of FGF21. Taken together, we hypothesize metformin increases FGF21 expression, and subsequently promotes expression of ABCA1 and ABCG1 in macrophages, which promotes cholesterol efflux from macrophages and attenuated atherosclerotic plaques. Further exploring cardioprotective mechanism of metformin will be useful for insight into novel therapeutic targets.

Dyslipidemia has been proven to play an important role in the occurrence and development of the ischemic stroke and lipid-lowering therapy could significantly decrease the risk of the ischemic stroke. However, the association between lipid levels, lipid-lowering therapy and the risk of intracerebral hemorrhage (ICH) is not clear. Studies have shown that low serum levels of total cholesterol might be associated with increasing risk of ICH, whereas the SPARCL study, a large prospective, randomized, placebo-controlled trial, demonstrated an increased risk of hemorrhagic stroke during high-dose statin therapy among the patients with previous stroke. The relationship between lipid-lowering therapy and ICH has become a hot topic in the recent years. We searched PubMed for articles published in English to review the existing evidence on the association of lipid levels, statin therapy and risk of ICH as well as the underlying mechanisms in order to provide practical recommendations for clinical decision-making and a foundation for further researches.

Background Statin-fibrate combination therapy has been used to treat patients with acute coronary syndrome (ACS) complicated by elevated triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C). The purpose of this study was to evaluate the influence of the combination therapy on lipids profile and apolipoprotein A5 (apoA5) level in patients with ACS. Methods One hundred and four patients with ACS were recruited and randomly assigned into two groups: one was statin group (n = 52), given atorvastatin (20 mg QN) or other statins with equivalent dosages; the other was combination group (n = 52), given the same dose of statin plus bezafibrate (200 mg BID). Follow-up visits were scheduled at the end of 6 and 12 weeks post treatment. Serum apoA5 levels were determined using a commercial available ELISA kit. Results (1) Compared with that of statin monotherapy, statin-bezafibrate combination treatment not only resulted in a significant reduction of TG, TC and LDL-C levels, (all p p (2) The percentage changes of TC, TG, LDL-C and apoA5 levels in both groups were even bigger at 12 weeks after treatment than that at 6 weeks (all p p (3) Spearman rank correlation analysis showed that the pre-treatment apoA5 level was positively correlated with TG (r = 0.359, p = 0.009). However, a negative correlation was observed between apoA5 and TG (r = -0.329, p = 0.017) after 12 weeks treatment. Conclusions Statin and fibrate combination therapy is more effective than statin alone in achieving a comprehensive lipid control for ACS patients. Serum apoA5 elevation after statin and fibrate combination treatment could be due to the synergistic effect of both drugs on hypertriglyceridemia control.