Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice.

BACKGROUND: High-mobility group box protein 1 (HMGB1) is known to have proinflammatory properties; however, the mechanisms by which HMGB1 influences immune responses during atherosclerosis (AS) development are not well understood. Thus, this study investigated the relationship between HMGB1 and vascular inflammation in Apoe-/- mice and whether glycyrrhizin (GLY), a small inhibitor of HMGB1, could have atheroprotective effects in AS. METHODS: Apoe-/- mice on a high-fat diet were treated with GLY (50 mg/kg) or vehicle by gavage once daily for 12 weeks, respectively. RESULTS: The GLY group exhibited significantly decreased serum lipid levels, atherosclerotic plaque deposition, and serum HMGB1 levels, as well as an increased Treg/Th17 ratio. The GLY group displayed increased interleukin-10 (IL-10) and IL-2 expression and decreased IL-17A and IL-6 expression. Furthermore, the GA treatment significantly reduced STAT3 phosphorylation in Th17 cells and increased STAT5 phosphorylation in Treg cells. CONCLUSIONS: Our findings indicate that the attenuation of atherosclerotic lesions in Apoe-/- mice by GLY might be associated with the amelioration of lipid metabolism abnormalities, inhibition of HMGB1 expression, and alterations in the Treg/Th17 ratio.

The Effects of High Mobility Group Box-1 Protein on Peripheral Treg/Th17 Balance in Patients with Atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is defined as chronic inflammation of the vessel wall. The major objective of the this study was to explore the mechanism of Treg/Th17 imbalance and the role of high mobility group box-1 protein (HMGB1) on the balance in AS. METHODS: We detected the apoptotic ratios of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects with AS and normal coronary arteries (NCA) by flow cytometry. The effects of recombinant HMGB1 (rHMGB1) on the proportion, apoptosis and differentiation of Treg and Th17 cells were analyzed using flow cytometry, qRT-PCR and ELISA. RESULTS: The frequencies of apoptotic Treg cells in the PBMCs from the subjects with AS were significantly higher than in those with NCA (p < 0.01). Stimulation of rHMGB1 obviously increased the level of Th17 cells and acid- related orphan receptor C (RORC) mRNA, and markedly decreased Treg cell frequency and the mRNA expression of factor forkhead family protein 3 (Foxp3) in the PBMCs. rHMGB1 played an obvious role in elevating Treg cell apoptosis ratio (p < 0.01). rHMGB1 treatment significantly decreased Treg cell ratio and IL-10 level, and increased Th17 cell ratio and IL-17A level induced from naïve CD4+ T cells. CONCLUSIONS: HMGB1 may modulate Treg/Th17 balance in patients with AS through inducing Treg cell apoptosis and promoting cell differentiation of Th17.

Abnormal circadian rhythms are associated with plaque instability in acute coronary syndrome patients.

AIM: Acute coronary syndrome (ACS), a leading cause of morbidity and mortality worldwide, is among the most serious cardiovascular diseases. Circadian rhythms are present in almost all organisms. In clinical practice, we have found that ACS is closely related to these circadian rhythms. However, the relationship between circadian rhythms and plaque instability in ACS patients is incompletely understood. The aim of this study is to provide new insights into the relationship between circadian rhythms and plaque instability in ACS patients. METHODS: We enrolled patients with ACS and individuals with normal coronary artery function in this study. The Athens Insomnia Scale (AIS), Pittsburgh Sleep Quality Index (PSQI), International Physical Activity Questionnaire (IPAQ) and Healthy Diet Score (HDS) were used to evaluate circadian rhythms. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the mRNA expression levels of muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), Cryptochrome1 (Cry1), Period2 (Per2), nuclear receptor subfamily 1, group D, member 1 (Rev-erbα), and matrix metalloproteinases MMP2 and MMP9. RESULTS: AIS scores and PSQI scores were significantly higher in patients with ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UA) than in the normal controls (NCs) (P < 0.05). The IPAQ scores of the NCs and patients with UA were significantly higher than in patients with STEMI and NSTEMI (P < 0.05). Notably higher HDS scores were recorded for the NCs compared to those of patients with UA, NSTEMI, and STEMI (P < 0.05). Consistent with these findings, compared with the NCs, the lowest levels of Bmal1, Clock, Cry1, Per2 and Rev-erbα mRNAs were detected in patients with STEMI, followed by patients with NSTEMI and then patients with UA (P < 0.05). Furthermore, the levels of MMP2 and MMP9 mRNA were significantly higher in the patients with STEMI, NSTEMI, and UA than those in the NCs (P < 0.05). In addition, we found that the levels of MMP mRNA negatively correlated with the levels of clock genes mRNAs (P < 0.05, respectively). CONCLUSIONS: Based on our data, the circadian rhythms and clock genes are correlatively with the occurrence of ACS, and the expression levels of clock genes are negatively correlated with plaque stability in ACS patients.

Long noncoding RNAs and atherosclerosis.

Atherosclerosis is universally recognized as a chronic lipid-induced inflammation of the vessel wall in response to dyslipidemia and haemodynamic stress involving dysfunction and activation of resident vascular cells as well as infiltration of leukocytes. As members of nonprotein-coding RNAs, the long noncoding RNAs (lncRNAs) are implicated in various biological processes. Accumulating evidences suggest that lncRNAs regulate the function of vascular wall, activation of macrophages, lipid metabolism and immune response. Here, we review the effects of lncRNAs on the progress of atherosclerosis.

HMGB1Modulates the Treg/Th17 Ratio in Atherosclerotic Patients.

AIM: Atherosclerosis (AS) characterized as a chronic inflammatory disease. Multiple immune cells and inflammatory cytokines, such as high mobility group protein (HMGB1), regulatory T (Treg) cells, T helper (Th17) cells, and inflammation-related cytokines, play a key role in its pathophysiology. A large number of studies report that HMGB1 and Th17 cells may promote atherosclerosis progression, whereas Treg cells may play a protective role in atherosclerosis; thus, alterations in the Treg/Th17 ratio may exist in atherosclerosis diseases. Up till now, the relationships between HMGB1 levels and the Treg/Th17 ratio remain incompletely understood. The major purpose of this study was to investigate the relationship between HMGB1 levels and the Treg/Th17 ratio in patients with coronary artery atherosclerotic plaques. METHODS: We enrolled patients with coronary atherosclerosis and normal coronary artery as the research subjects. Flow cytometry was used to analyze the Treg cells, the Th17 cells frequency, and the Treg/Th17 ratio. Otherwise, real-time polymerase chain reaction was used for assays the mRNA expressions of HMGB1, retinoic acid-related orphan nuclear receptor C (RORC), and forkhead-winged helix transcription factor (Foxp3). Moreover, enzyme-linked immunosorbent assays were used to detect the level of protein and cytokines, such as HMGB1, IL-10, TGF-ß1, IL-17A, and IL-23. RESULTS: Using flow cytometry, we observed a significantly increased of Th17 cell frequency, whereas Treg cell frequency significantly decreased in atherosclerotic patients. Consistently, the levels of RORC mRNA were significantly increased in coronary atherosclerosis (AS) group compared to normal coronary artery (NCA) group (P＜0.01). In contrast, the expression of Foxp3 mRNA was markedly lower in the AS group than in the NCA group (P＜0.01). Furthermore, we observed the serum concentrations of HMGB1, IL-17A, and IL-23 were significantly higher in the AS group than in the NCA group (P＜0.01, respectively), whereas the concentrations of serum IL-10 and TGF-ß1 were significantly lower in the AS group than in the NCA group (P＜0.01, respectively). In addition, we also found that HMGB1 levels showed negative correlation with the Treg/Th17 ratio in the two groups (r=－0.6984, P＜0.01). CONCLUSIONS: The data in our study indicated that HMGB1 may promote atherosclerosis progression via modulating the imbalance in the Treg/Th17 ratio.

Histone deacetylases and atherosclerosis.

Atherosclerosis is the most common pathological process that leads to cardiovascular diseases, a disease of large- and medium-sized arteries that is characterized by a formation of atherosclerotic plaques consisting of necrotic cores, calcified regions, accumulated modified lipids, smooth muscle cells (SMCs), endothelial cells, leukocytes, and foam cells. Recently, the question about how to suppress the occurrence of atherosclerosis and alleviate the progress of cardiovascular disease becomes the hot topic. Accumulating evidence suggests that histone deacetylases(HDACs) play crucial roles in arteriosclerosis. This review summarizes the effect of HDACs and HDAC inhibitors(HDACi) on the progress of atherosclerosis.