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Inflammatory responses in macrophages, endothelial cells, and vascular smooth muscle cells play crucial roles in the development of atherosclerosis. Baicalein, a flavonoid phytochemical, possesses anti-inflammatory properties, but the underlying mechanisms of its action are not fully understood. The aim of this study was to explore whether baicalein inhibited inflammatory activities in RAW264.7, HUVEC, and MOVAS cells and to analyze its underlying mechanisms. Our results showed that baicalein treatment effectively reduced the levels of IL-6, TNF-α, PAI-1, and MMP-9 released by these cells upon stimulation with Ang II or ox-LDL. We discovered that the molecular mechanisms underlying baicalein suppression of the generation of proinflammatory cytokines were associated with the inhibition of MAPK/NF-κB pathway activity. Moreover, Ang II and ox-LDL intervention decreased the content of Mfn-2 in the three types of cells, but incubation of baicalein alleviated the Ang II/ox-LDL-induced reduction of Mfn-2 levels. Adv-Mfn2 treatment not only increased the expression of Mfn-2 but also reduced the levels of phosphorylated ERK1/2, p38, JNK, and NF-κB, followed by a decrease in the concentrations of IL-6, TNF-α, PAI-1, and MMP-9 in the supernatant. Furthermore, our findings indicated that baicalein treatment markedly suppressed the decrease in AMPK activity induced with Ang II and ox-LDL, and incubation with Compound C reversed the effects of baicalein on AMPK activation and Mfn-2 expression. In conclusion, our data suggest that baicalein shows anti-inflammatory properties, probably by activating the AMPK/Mfn-2 axis, accompanied by inhibition of downstream MAPKs/NF-κB signaling transduction., (© 2021 John Wiley & Sons, Ltd.)

Background: Atherosclerosis is a chronic vascular disease posing a great threat to public health. We investigated whether rosuvastatin (RVS) enhanced autophagic activities to inhibit lipid accumulation and polarization conversion of macrophages and then attenuate atherosclerotic lesions., Methods: All male Apolipoprotein E-deficient (ApoE -/- ) mice were fed high-fat diet supplemented with RVS (10 mg/kg/day) or the same volume of normal saline gavage for 20 weeks. The burden of plaques in mice were determined by histopathological staining. Biochemical kits were used to examine the levels of lipid profiles and inflammatory cytokines. The potential mechanisms by which RVS mediated atherosclerosis were explored by western blot, real-time PCR assay, and immunofluorescence staining in mice and RAW264.7 macrophages., Results: Our data showed that RVS treatment reduced plaque areas in the aorta inner surface and the aortic sinus of ApoE -/- mice with high-fat diet. RVS markedly improved lipid profiles and reduced contents of inflammatory cytokines in the circulation. Then, results of Western blot showed that RVS increased the ratio LC3II/I and level of Beclin 1 and decreased the expression of p62 in aortic tissues, which might be attributed to suppression of PI3K/Akt/mTOR pathway, hinting that autophagy cascades were activated by RVS. Moreover, RVS raised the contents of ABCA1, ABCG1, Arg-1, CD206 and reduced iNOS expression of arterial wall, indicating that RVS promoted cholesterol efflux and M2 macrophage polarization. Similarly, we observed that RVS decreased lipids contents and inflammatory factors expressions in RAW264.7 cells stimulated by ox-LDL, accompanied by levels elevation of ABCA1, ABCG1, Arg-1, CD206 and content reduction of iNOS. These anti-atherosclerotic effects of RVS were abolished by 3-methyladenine intervention. Moreover, RVS could reverse the impaired autophagy flux in macrophages insulted by chloroquine. We further found that PI3K inhibitor LY294002 enhanced and agonist 740 Y-P weakened the autophagy-promoting roles of RVS, respectively., Conclusions: Our study indicated that RVS exhibits atheroprotective effects involving regulation lipid accumulation and polarization conversion by improving autophagy initiation and development via suppressing PI3K/Akt/mTOR axis and enhancing autophagic flux in macrophages.

Purpose: Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT., Methods: Male apoE -/- mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro., Results: HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE -/- mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% ( p = 0.004), 15.2% ( p = 0.003), and 17.9% ( p = 0.009), respectively, as well as hepatic TG and TC by 15.0% ( p < 0.001) and 12.3% ( p = 0.003), respectively, while inducing a 26.9% ( p = 0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF- α , IL-1 β , and IL-6 approximately by 23.5% ( p < 0.001), 27.8% ( p < 0.001), 18.4% ( p < 0.001), and 19.1% ( p < 0.001), respectively, and induced a 1.4-fold increase in IL-10 level ( p = 0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF- κ B, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation., Conclusion: Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Xinxin Zhang et al.)

Epidemiological studies have demonstrated that cardiovascular diseases (CVDs) are the leading cause of death in the world. Atherosclerosis, a kind of chronic vascular disorder related to multiple pathogenic processes, has been reported to be an underlying cause of CVDs. Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine formulation and has been broadly used for the treatment of CVDs in East Asia. However, whether SBP affects the development of atherosclerosis is poorly understood. The aim of this study was to investigate the antiatherosclerotic roles and relevant mechanisms of SBP in apolipoprotein E knockout mice. Our results showed that SBP treatment markedly decreased the size of atherosclerotic plaques of the entire aorta and the aortic sinus. Biochemical analyses indicated that SBP gavage improved oxidative stress in vivo, as seen by the level elevation of SOD, CAT, and GSH and the level reduction of MDA, H 2 O 2 , and MPO. Moreover, the concentration of MCP-1, IFN- γ , and IL-17A was reduced, and the content of IL-10 and TGF- β 1 was increased in the serum from SBP-treated mice. We discovered that the expression levels of inflammatory factors including VCAM-1, ICAM-1, IL-6, and IL-2 in the vascular wall of the SBP group were also decreased in comparison with those of the normal saline group. Moreover, we found that SBP alleviated the activation of inflammation-related pathways in the aorta tissue, as seen by the level elevation of Mfn2 and reduced phosphorylation of p38, JNK, and NF- κ B. Furthermore, western blot showed that SBP administration reduced the level of SR-A and LOX-1 and elevated the content of LXR α , ABCA1, and ABCG1 in the arterial wall, indicating that SBP was capable of alleviating lipid influx and facilitating lipid efflux. In conclusion, our data suggested that SBP exerted antiatherosclerotic effects via improving inflammation response and inhibiting lipid accumulation.

Atherosclerosis, a chronic luminal stenosis disorder occurred in large and medium arteries, is the principle pathological basis of cardiovascular diseases with the highest morbidity and mortality worldwide. In oriental countries, traditional Chinese medicine Cortex Moutan has been widely used for the treatment of atherosclerosis-related illnesses for thousands of years. Paeonol, a bioactive monomer extracted from Cortex Moutan, is an important pharmacological component responsible for the antiatherosclerotic effects. Numerous lines of findings have established that paeonol offers beneficial roles against the initiation and progression of atherosclerotic lesions through inhibiting proatherogenic processes, such as endothelium damage, chronic inflammation, disturbance of lipid metabolism, uncontrolled oxidative stress, excessive growth, and mobilization of vascular smooth muscle cells as well as abnormality of platelet activation. Investigations identifying the atheroprotective effects of paeonol present substantial evidence for potential clinical application of paeonol as a therapeutic agent in atherosclerosis management. In this review, we summarize the antiatherosclerotic actions by which paeonol suppresses atherogenesis and provide newly insights into its atheroprotective mechanisms and the future clinical practice.

Cardiovascular diseases (CVDs) are considered to be the predominant cause of death in the world. Chinese herb medicines (CHMs) have been widely used for the treatment of CVDs in Asian countries for thousands of years. One reason of high efficacy of CHMs in treating CVDs is attributed to their inhibition in atherosclerosis (AS) development, a critical contributor to CVDs occurrence. Cumulative studies have demonstrated that CHMs alleviate atherogenesis via mediating pathophysiologic events involved in AS. However, there is deficiency in the summaries regarding antiatherogenic signal pathways regulated by CHMs. In this review, we focus on the signal cascades by which herb medicines and relevant extractives, derivatives, and patents improve proatherogenic processes including endothelium dysfunction, lipid accumulation, and inflammation. We mainly elaborate the CHMs-mediated signaling pathways in endothelial cells, macrophages, and vascular smooth muscle cells of each pathogenic event. Moreover, we briefly describe the other AS-related factors such as thrombosis, autophagy, immune response, and noncoding RNAs and effects of CHMs on them in the way of cascade regulation, which is helpful to further illustrate the molecular mechanisms of AS initiation and progression and discover newly effective agents for AS management.

The aim of this study is to discuss the hypothesis that expression of plasma atherosclerosis-associated microRNAs (miRNAs) in hyperhomocysteinemia (Hhcy) patients could predict the presence of atherosclerosis from different channels. Six plasma miRNAs (miR-145, miR-155, miR-222, miR-133, miR-217, and miR-30) selected for our study have been confirmed as critical gene regulators involved in atherosclerosis and can be steadily determined in plasma. Expression of the above six plasma circulating miRNAs revealed significant upregulation of two miRNAs (miR-133 and miR-217) and downregulation of three miRNAs (miR-145, miR-155, and miR-222). Six candidate miRNAs showed a significant correlation with homocysteine (Hcy) or lipid parameters. The results of this study indicated that miR-217 was further significantly upregulated in Hhcy + ATH groups than in normal control, Hhcy-, and atherosclerosis-alone (ATH) groups and it showed a significant negative correlation with Hcy and triglycerides. More specifically, miR-217 showed the most specific expression patterns in all patients with atherosclerosis (ATH and Hhcy + ATH groups), which may have been a diagnostic value for Hhcy complicated with atherosclerosis, and predicted the progress of atherosclerosis in Hhcy patients effectively.

Background: An elevated level of homocysteine (Hcy) in the blood is designated hyperhomocysteinaemia (Hhcy) and is regarded as a strong risk factor for the development of atherosclerosis (ATH), although the association remains controversial. Considered to be essential gene expression regulators, micro-RNAs (miRNAs) modulate cardiovascular disease development and thus can be regarded as potential biomarkers and therapeutic targets in atherosclerosis. The aim of the current study is to investigate the expression levels of atherosclerosis-associated miR-143 and miR-145 in Hhcy patients and predict the progress of atherosclerosis in Hhcy patients.Methods: A total of 100 participants were enrolled and included normal control subjects (NC = 20), hyperhomocysteinaemia alone subjects (Hhcy = 25), hyperhomocysteinaemia and carotid artery atherosclerosis combined subjects (Hhcy + ATH = 30) and patients with standalone carotid artery atherosclerosis (ATH = 25). Plasma Hcy, supplementary biochemical parameters and carotid artery ultrasonography (USG) were measured in all participants. MicroRNA expression levels in the peripheral blood were calculated by real-time reverse transcription-polymerase chain reaction (qRT-PCR). The correlations of miR-143 and miR-145 with Hcy, blood lipid parameters and carotid artery atherosclerotic plaques were evaluated using Pearson's correlation coefficients. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the capacities of miR-143 and miR-145 for the detection of Hhcy and atherosclerosis patients.Results: MiR-143 and miR-145 exhibited trends towards significance with stepwise decreases from the NC to Hhcy groups and then to the Hhcy + ATH and ATH groups. Similar results were observed in the carotid artery plaque group (Hhcy + ATH and ATH grups) compared with the no-plaque group (NC and Hhcy groups). The miR-143 expression level exhibited significant negative correlations with Hcy, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c). The miR-145 expression level exhibited significant negative correlations with Hcy, TC, triglyceride (TG) and LDL-c. MiR-143 and miR-145 exhibited the greatest area under the curves (AUCs) (0.775 and 0.681, respectively) for the detection of every Hhcy patient, including those in the Hhcy and Hhcy + ATH groups, from among all subjects.Conclusion: The results indicated that the levels of atherosclerosis-associated circulating miR-143 and miR-145 are linked to Hhcy. MiR-143 may be used as a potential non-invasive biomarkers of Hhcy and thus may be helpful in predicting the progress of atherosclerosis in Hhcy patients. [ABSTRACT FROM AUTHOR]