Equisetin protects from atherosclerosis in vivo by binding to STAT3 and inhibiting its activity.

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid metabolism disorder and lipid accumulation. Equisetin (EQST) is a hemiterpene compound isolated from fungus of marine sponge origin, which has antibacterial, anti-inflammatory, lipid-lowering, and weight loss effects. Whether EQST has anti-atherosclerotic activity has not been reported. In this study, we revealed that EQST displayed anti- atherosclerosis effects through inhibiting macrophage inflammatory response, lipid uptake and foam cell formation in vitro, and finally ameliorated high-fat diet (HFD)-induced atherosclerosis in AopE-/- mice in vivo. Mechanistically, EQST directly bound to STAT3 with high-affinity by forming hydrophobic bonds at GLN247 and GLN326 residues, as well as hydrogen bonds at ARG325 and THR346 residues. EQST interacted with STAT3 physically, and functionally inhibited the transcription activity of STAT3, thereby regulating atherosclerosis. Therefore, these results supports EQST as a candidate for developing anti-atherosclerosis therapeutic agent.

Organic anion-transporting polypeptide 2B1 knockout and humanized mice; insights into the handling of bilirubin and drugs.

Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the roles of OATP2B1 in physiology and pharmacology, we established and characterized Oatp2b1 knockout (single Slco2b1-/- and combination Slco1a/1b/2b1-/-) and humanized hepatic and intestinal OATP2B1 transgenic mouse models. While viable and fertile, these strains exhibited a modestly increased body weight. In males, unconjugated bilirubin levels were markedly reduced in Slco2b1-/- compared to wild-type mice, whereas bilirubin monoglucuronide levels were modestly increased in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice. Single Slco2b1-/- mice showed no significant changes in oral pharmacokinetics of several tested drugs. However, markedly higher or lower plasma exposure of pravastatin and the erlotinib metabolite OSI-420, respectively, were found in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice, while oral rosuvastatin and fluvastatin behaved similarly between the strains. In males, humanized OATP2B1 strains showed lower conjugated and unconjugated bilirubin levels than control Slco1a/1b/2b1-deficient mice. Moreover, hepatic expression of human OATP2B1 partially or completely rescued the impaired hepatic uptake of OSI-420, rosuvastatin, pravastatin, and fluvastatin in Slco1a/1b/2b1-/- mice, establishing an important role in hepatic uptake. Expression of human OATP2B1 in the intestine was basolateral and markedly reduced the oral availability of rosuvastatin and pravastatin, but not of OSI-420 and fluvastatin. Neither lack of Oatp2b1, nor overexpression of human OATP2B1 had any effect on fexofenadine oral pharmacokinetics. While these mouse models still have limitations for human translation, with additional work we expect they will provide powerful tools to further understand the physiological and pharmacological roles of OATP2B1.

Targeting the residual cardiovascular risk by specific anti-inflammatory interventions as a therapeutic strategy in atherosclerosis.

Chronic subclinical inflammation is a key process in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Along with lipids, inflammation is essential for the initiation and progression of atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine secretion. Several pro-inflammatory cytokines have been described in the primary and secondary prevention of ASCVD. Although extensive work over the past decades has established the role of lipid-lowering medications in the prevention and treatment of ASCVD, modulation of inflammation is a subject of active debate. It remains to be confirmed whether targeting the residual cardiovascular risk by adding anti-inflammatory agents to the conventional cardiovascular treatment becomes a shifting paradigm for ASCVD management. This review aims to discuss novel therapeutic agents targeting inflammatory pathways in ASCVD in light of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial results. Further we discuss the effects of different anti-inflammatory agents administered in patients with ASCVD and their potential to change clinical practice in preventive cardiology.

Effect of statins on the risk of recurrent venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: Recent studies have suggested that statins may be associated with a lower risk of recurrent venous thromboembolism (VTE). METHODS: We systematically searched PubMed, Web of Science and Cochrane Library from inception until May 2020 to identify any eligible studies that reported the association between statin use and the risk of recurrent VTE, and conducted a comprehensive systematic review and meta-analysis (PROSPERO registration number: CRD42020190169) on this matter. RESULTS: A total of 14 observational studies were included for qualitative review and 12 of them qualified for meta-analyses. The main meta-analysis found that statin use was associated with a lower risk of disease recurrence among patients with VTE (pooled adjusted HR: 0.76, 95% CI: 0.69-0.83), which was robust in sensitivity analyses and free of significant publication bias. Additionally, such association was present when restricting to periods after anticoagulation withdrawal (pooled adjusted HR: 0.78, 95% CI: 0.70-0.88) and when separately analyzing recurrent deep vein thrombosis (pooled adjusted HR: 0.71, 95% CI: 0.62-0.81) and recurrent pulmonary embolism (pooled adjusted HR: 0.80, 95% CI: 0.66-0.97; P = 0.027). Furthermore, statin use in patients with VTE was also found to be associated with a lower risk of all-cause mortality (adjusted HR: 0.65, 95% CI: 0.56-0.77), and possibly an even lower risk of bleeding (adjusted HR: 0.88, 95% CI: 0.73-1.07), albeit not statistically significant. CONCLUSION: Statins have the potential to reduce recurrent events among patient with VTE. Randomized clinical trials to better explore the effect of statins in secondary prevention of VTE are warranted.

Effect of different types and dosages of statins on plasma lipoprotein(a) levels: A network meta-analysis.

BACKGROUND AND AIM: Studies differ with respect to the effects of statins and their on lipoprotein(a)[Lp(a)] levels. The aim of the present study was to resolve these differences by determining the effect of various types and dosages of statins on Lp(a) levels. METHODS: We searched PubMed, Embase and the Cochrane library for randomized controlled trials (RCTs) investigating the efficacy of statins on plasma Lp(a) levels. Study selection, data extraction and risk of bias assessment were conducted independently by four authors. We conducted pairwise meta-analysis and network meta-analysis (NMA). Consistency models were applied to NMA and the ranking probabilities for each treatment's efficacy were calculated. Node-splitting analysis was used to test inconsistency. This study was registered with PROSPERO, number CRD42020167612. RESULTS: Twenty RCTs with 23,605 participants were included, involving 11 interventions. Most of the included studies presented some risks of bias, especially risks of performance and detection bias. In the pairwise meta-analysis, pooled results showed a small but statistically significant difference between high-intensity rosuvastatin and placebo on Lp(a) levels (MD = 1.81, 95 % CI [0.43, 3.19], P = 0.01). In the NMA, different types and dosages of statins showed no significant effect on the level of Lp(a), and there was no obvious difference between them. Subgroup analysis based on different populations and treatment durations did not provide any statistically significant findings about different statins on Lp(a) levels. Node-splitting analysis showed that no significant inconsistency existed (P > 0.05). CONCLUSIONS: Statins have no clinically significant effect on Lp(a) levels, and there is no significant difference in the effect on Lp(a) levels between different types and dosages of statins. Moderate-intensity pitavastatin tended to have the best effect on reducing Lp(a) levels; nevertheless, it was insignificant. Our findings highlight the necessity for further study of the effect of statins on Lp(a) levels in future studies.

Rosuvastatin: Beyond the cholesterol-lowering effect.

Rosuvastatin is a fully synthetic statin wich acts by interfering with the endogenous synthesis of cholesterol through competitively inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a liver enzyme responsible of the rate-limiting step in cholesterol synthesis. When compared to other molecules of the same class, it shows high efficacy in the improvement of lipid profile, and, thanks to its non-cholesterol-lowering actions (anti-inflammatory, antioxidant and antithrombotic), represents a crucial tool for cardiovascular primary and secondary prevention. Moreover, recent data highlight rosuvastatin beneficial effects in several other fields. In this manuscript we analyzed literature sources in order to better define rosuvastatin features and discuss some critical issues.

Differential changes in the pharmacokinetics of statins in collagen-induced arthritis rats.

The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins.

Cyclooxygenase inhibition and rosuvastatin-induced vascular protection in the setting of ischemia-reperfusion: A human in vivo study.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors have preconditioning effects involving up-regulation of cyclooxygenase (COX)-2. We investigated the effect of selective and non-selective COX inhibition on rosuvastatin-mediated protection against ischemia-reperfusion (IR)-induced endothelial dysfunction in the human forearm. Healthy volunteers (n=66) were allocated to placebo, acetylsalicylic acid (ASA) 81mg daily, ASA 325mg daily, celecoxib 200mg twice daily or 400mg ibuprofen four times daily, each administered for 5 to 7days. On the last day of study drug therapy, subjects received a single dose of 40mg rosuvastatin. Twenty-four hours later flow-mediated dilation (FMD) of the radial artery was evaluated before and after IR. In the placebo group, FMD was similar before and after IR (8.1±1.0 vs 7.2±0.8%; P=NS) indicating a significant protective effect of rosuvastatin. There was also no effect of IR on FMD in the ASA 81mg group (6.7±0.6 vs 6.1±0.7%; P=NS). In contrast, following IR there was a significant decrease in FMD in the ASA 325mg group (7.2±0.8 vs 3.3±0.7%, P<0.001), the celecoxib group (7.3±1.5 vs 2.6±1.5%, P<0.01) as well as the ibuprofen group (6.8±0.7 vs 2.6±0.8%; P<0.01). Therefore, nonselective COX inhibition with ASA 325mg and ibuprofen completely inhibit the protective effects of rosuvastatin in the setting of IR injury, as does therapy with the specific COX-2 antagonist celecoxib. In contrast, therapy with low dose ASA (81mg daily) does not have such inhibitory effects.