Sacubitril/Valsartan Cannot Improve Cardiac Function Compared with Valsartan in Patients Suffering Nonvalvular Atrial Fibrillation without Systolic Heart Failure.

This study investigates the effect of sacubitril/valsartan (Sac/Val) in patients diagnosed with nonvalvular atrial fibrillation (AF) without systolic heart failure (SHF).Nonvalvular AF patients without SHF admitted to the People's Hospital of Bortala Mongol Autonomous Prefecture from December 2020 to December 2021 were enrolled and randomly divided into Sac/Val treatment group (group T) and valsartan treatment group (group C, control). For subgroup analysis, patients were divided into subgroups with and without diastolic heart failure (DHF). After 1-month adaptive phase and subsequent 3-month treatment period, patients were followed up in the cardiology clinic. Plasma levels of biochemical markers and echocardiographic parameters before and after treatment were evaluated, and DHF scores were computed to assess diastolic function.Of 61 enrolled patients, 46 patients completed follow-up. Sac/Val treatment did not increase the percentage of sinus rhythm. Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) expression tended to be reduced in both groups after 3 months of treatment, the differences compared with respective baseline levels and between groups were not significant. According to subgroup analysis, although NT-proBNP expression in the subgroup with DHF was lower at follow-up compared to baseline, the difference was not statistically significant. Similarly, no marked differences in echocardiographic parameters or tissue Doppler parameters related to DHF were detected between the groups (P > 0.05). Additionally, a subgroup analysis found no significant variations in the echocardiographic measures (P > 0.05).Sac/Val is not superior to valsartan for the short-term treatment of patients suffering with AF without SHF in improving NT-proBNP level and cardiac function.

Analysis of the genetic association between IL27 variants and coronary artery disease in a Chinese Han population.

Interleukin-27 (IL-27) is an important cytokine in inflammatory diseases, including coronary artery disease (CAD). To explore the precise role of IL-27 in CAD, we investigated the genetic association between IL27 and CAD in the GeneID Chinese Han population. A two-stage case control association analysis was performed for 3075 CAD cases and 2802 controls. Logistic regression analysis was used to adjust the traditional risk factors for CAD. Results showed that a promoter variant, rs153109, tended to be marginally associated with CAD in the discovery population (Padj = 0.028, OR = 1.27, 95%CI: 1.03-1.58). However, this association was not replicated in the validation stage (Padj = 0.559, OR = 1.04, 95%CI: 0.90-1.21). In addition, when we classified the combined population into two subgroups according to the age at disease onset or disease state, we again obtained no significant associations. Finally, we estimated the severity of coronary stenosis using the Gensini Scoring system and determined that the rs153109 genotypes were still not associated with the Gensini scores of the CAD patients. In conclusion, our study failed to find an association between common variants in the functional region of IL27 and CAD in a Chinese Han population, which indicated that IL-27 might only be an inflammatory marker during the development of CAD.

Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties.

Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 ± 5.11, 6.92 ± 0.95 µM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 µM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca(2+) influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-κB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

MicroRNA-21 negatively regulates Treg cells through a TGF-ß1/Smad-independent pathway in patients with coronary heart disease.

BACKGROUND: CD4+CD25+FoxP3+ regulatory T cells (Treg cells) play a protective role against the development and progression of the inflammatory disease atherosclerosis (AS). MicroRNA-21 (miR-21) is expressed in Treg cells and is up-regulated in the context of AS and other inflammatory diseases. AIMS: This study aimed to determine the role of miR-21 in Treg cell regulation and gene expression during the development of AS in patients with coronary heart disease (CHD). METHODS AND RESULTS: MiR-21 expression in peripheral blood mononuclear cells (PBMCs) was significantly up-regulated in patients with CHD (acute myocardial infarction (AMI) group, n=24; unstable angina (UA) group, n=21; stable angina (SA) group, n=24) compared with patients with chest pain syndrome (CPS, n=27), and miR-21 expression showed an increasing trend from SA to UA to AMI patients. Moreover, flow cytometry analysis indicated that the frequencies of circulating Treg cells decreased in a manner proportionate opposite with the level of miR-21. Quantitative real-time PCR (qRT-PCR) revealed a decrease in mRNA expression of forkhead box P3 (foxp3), transforming cell growth factor beta 1(TGF-ß1) and smad7 (a known target gene of miR-21). ELISA analysis revealed a decrease in TGF-ß1 secreted into the plasma. In addition, we transfected PBMCs with a miRNA negative control (NS-m), a miR-21 mimic (miR-21-m), a miRNA inhibitor negative control (NS-i), or a miR-21 inhibitor(miR-21-i). Up-regulation of miR-21 decreased the frequency of circulating Treg cells, decreased the expression levels of foxp3, TGF-ß1 and smad7, and decreased the amount of TGF-ß1 secreted into the plasma. Consistent with these observations, miR-21 down-regulation increased the frequency of circulating Treg cells, increased the expression of foxp3, TGF-ß1 and smad7, and increased the amount of TGF-ß1 secreted into the plasma. CONCLUSIONS: Because the smad7 expression pattern was similar to that of TGF-ß, our study suggests that miR-21 can negatively regulate the frequency of circulating Treg cells through a TGF-ß1/smad-independent signaling pathway in PBMCs.

Impaired thymic export and apoptosis contribute to regulatory T-cell defects in patients with chronic heart failure.

OBJECTIVE: Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients. METHODS AND RESULTS: We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p<0.01), CD4(+)CD25(+)FOXP3(+)CD45RO(-) CD45RA(+)CD31(+) recent thymic emigrant T(reg) cell (RTE-T(reg)) frequency (p<0.01), and T-cell receptor excision circle levels in T(reg) cells (p<0.01) were lower in CHF patients than in non-CHF controls. Combined annexin-V and 7-AAD staining showed that peripheral T(reg) cells from CHF patients exhibited increased spontaneous apoptosis and were more prone to interleukin (IL)-2 deprivation- and CD95 ligand-mediated apoptosis than those from non-CHF individuals. Furthermore, analyses by both flow cytometry and real-time polymerase chain reaction showed that T(reg)-cell frequency in the mediastinal lymph nodes or Foxp3 expression in hearts of CHF patients was no higher than that of the non-CHF controls. CONCLUSION: Our data suggested that the T(reg)-cell defects of CHF patients were likely caused by decreased thymic output of nascent T(reg) cells and increased susceptibility to apoptosis in the periphery.

Inhibition of IL-17A in atherosclerosis.

OBJECTIVE: To determine the effects of interleukin (IL)-17A inhibition on experimental atherosclerosis. METHODS AND RESULTS: ApoE(-/-) mice were treated with either rat anti-mouse IL-17A, mouse anti-mouse IL-17A or isotype-matched control antibodies for 12 weeks (n=8-10 per group). Ldlr(-/-) mice were transplanted with IL-17A-deficient or wild type bone marrow (n=8 per group). Rat anti-mouse IL-17A treatment obviously reduced plaque size by 43% (p<0.01) without evidence of reduced IL-17A signaling. In contrast, mouse anti-mouse IL-17A treatment and IL-17A deficiency in bone marrow cells did not alter lesion size despite significant reduction of IL-17A production. CONCLUSIONS: Inhibition of IL-17A signaling does not alter lesion development in Th1-biased C57BL/6 ApoE(-/-) and Ldlr(-/-) mice with already low levels of IL-17A production. Alteration of lesion development after repeated injections of rat anti-mouse IL-17A antibody in ApoE(-/-) mice could not be attributed to blockade of IL-17A signaling.

Improved cardiac performance by rosuvastatin is associated with attenuations in both myocardial tumor necrosis factor-alpha and p38 MAP kinase activity in rats after myocardial infarction.

INTRODUCTION: Statins have been shown to exert anti-inflammatory effects. The aim of this study was to investigate whether rosuvastatin has favorable effect on ventricular remodeling after myocardial infarction (MI), whether this effect is associated with tumor necrosis factor (TNF)-alpha expression and p38 mitogen-activated protein (MAP) kinase pathway and, furthermore, whether there is close correlation between gene expression of TNF-alpha and activity of p38 MAP kinase. METHODS AND RESULTS: Adult male Wistar rats with acute MI were randomly divided into 2 groups: (1) rosuvastatin-treated group (MI-R) receiving rosuvastatin 20 mg/kg once daily, and (2) infarcted group (MI) receiving saline, when compared with sham-operated control group. Four weeks later, echocardiography, hemodynamics and Van Gieson staining were applied to evaluate left ventricular remodeling and cardiac function. Myocardial gene expression of TNF-alpha and activity of p38 MAP kinase were analyzed by real time-polymerase chain reaction and Western blot, respectively. The results demonstrated that increased TNF-alpha gene expression in noninfarcted areas was accompanied by activation of p38 MAP kinase pathway. Moreover, treatment of rosuvastatin markedly improved ventricular remodeling and cardiac function in rats, which was associated with attenuations in both TNF-alpha gene expression and p38 MAP kinase activity in myocardium without changes in serum lipid levels. CONCLUSIONS: Treatment of rosuvastatin was able to improve cardiac remodeling and cardiac function after acute MI, which was associated with attenuations in both expression of TNF-alpha and activity of p38 MAP kinase in myocardium.

Defective circulating CD4CD25+Foxp3+CD127(low) regulatory T-cells in patients with chronic heart failure.

AIMS: Increasing evidences confirm the role of immune activation in the pathogenesis of chronic heart failure (CHF). Regulatory T cells appear central to the control of immune homeostasis. We assessed the hypothesis that the circulating frequency and function of CD4+CD25+ Foxp3+CD127(low) T regulatory cells (Tregs) would be deranged in patients with CHF. METHODS: Ninety-nine CHF patients due to non-ischemic (NIHF) or ischemic etiology (IHF) and 24 control donors were enrolled in the study. Frequency of circulating Tregs was evaluated by flow cytometry. Foxp3 in peripheral blood mononuclear cells (PBMCs) was assayed at the mRNA level by real-time PCR. Functional properties of Tregs to suppress proliferation and pro-inflammatory cytokines secretion of activated CD4+CD25(-) T cells were measured by proliferation assay and ELISA. RESULTS: The results demonstrated that CHF patients had significantly lower frequency of circulating Tregs and reduced Foxp3 expression in PBMCs compared with control donors. Moreover, Tregs from CHF patients showed compromised function to suppress CD4+CD25(-) T cells proliferation and pro-inflammatory cytokines secretion. A similar pattern with reduced Tregs frequency and compromised function was found in both NIHF and IHF patients. Correlation analysis suggested that Tregs frequency and function positively correlated with LVEF, whereas negatively correlated with LVEDD and NT-proBNP in patients with CHF. CONCLUSIONS: Our data are the first to demonstrate that frequencies of circulating Tregs in patients with CHF are reduced and their suppressive function compromised independently of the etiology. Defective Tregs may be an underlying mechanism of immune activation in CHF patients.

The Th17/Treg functional imbalance during atherogenesis in ApoE(-/-) mice.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets. Recently, CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells and Th17 cells have been described as two distinct subsets and have the opposite effects on autoimmunity. Clinical observation has revealed that the Th17/Treg imbalance exists in patients with acute coronary syndrome. We investigated whether the Th17/Treg functional imbalance existed during atherogenesis in ApoE(-/-) mice. METHODS AND RESULTS: Th17/Treg functions at different levels including cell frequencies, related cytokine secretion and key transcription factors were investigated comparatively between ApoE(-/-) mice and their age-matched C57BL/6J mice. The results demonstrated that ApoE(-/-) mice revealed significantly increased secretion of Th17 related cytokines (IL-17 and IL-6) and expression of transcription factor (RORgammat) levels and obviously decreased number in Treg cells, secretion of Treg related cytokines (TGF-beta(1)) and expression of transcription factor (Foxp3) levels as compared with age-matched C57BL/6J mice. Th17 related mediators reached their maximum expression values at the early stage (8-16weeks of age) in ApoE(-/-) mice, and then followed by continuous depression of their expression levels. Meanwhile, the expression of Treg related mediators was much lower in ApoE(-/-) mice than in their age-matched wild-type littermates. CONCLUSIONS: Th17/Treg functional imbalance exists during atherogenesis in ApoE(-/-) mice, suggesting a potential role of Th17/Treg imbalance in the formation and progression of atherosclerosis.

Molecular mechanisms of irbesartan suppressing atherosclerosis in high cholesterol-diet apolipoprotein E knock-out mice.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease in which the renin-angiotensin-aldosterone system plays an important role. Evidence indicate that the angiotensin type 1 receptor blockers can suppress atherogenesis, but the exact mechanisms have not been fully elucidated. The study was undertaken to investigate the potential effects and molecular mechanisms of an angiotensin type 1 receptor blocker irbesartan on atherogenesis in high cholesterol-diet apolipoprotein E knock-out mice. METHODS AND RESULTS: Adult male apolipoprotein E knock-out mice were given normal diet or high cholesterol-diet and randomized to receive no treatment or irbesartan 10 mg kg(-1) d(-1) for 12 weeks. The apolipoprotein E knock-out mice with high cholesterol-diet were associated with a marked increase in atherosclerotic lesion area, plasma lipid and angiotensin II levels, as well as the expressions of angiotensin type 1 receptor in the aorta. High cholesterol-diet feeding increases the activity of NADPH oxidase subunits (p47(phox) and Rac), extracellular signal-regulated kinase 1/2, janus kinase 2, signal transducer and activator of transcription 3, nuclear factor-kappaB and the expression of tumor necrosis factor-alpha, interleukin 6, monocyte chemoattactant protein-1 and vascular cell adhesion molecule-1 in the aortas. These changes were suppressed in mice that were treated with irbesartan 10 mg kg(-1) d(-1), with no significant change in systolic blood pressure and plasma lipid levels. CONCLUSIONS: The results suggest that irbesartan can attenuate atherosclerosis, and this effect is partly related to the inhibition of oxidative stress and inflammatory signal transduction pathways which eventually leads to the decrease in the expression of inflammatory cytokines.

Poly (ADP-Ribose) polymerase inhibition attenuates atherosclerotic plaque development in ApoE-/- mice with hyperhomocysteinemia.

AIM: Hyperhomocysteinemia (Hhcy) is an important and independent risk factor for atherosclerosis. Recent studies have shown that Poly (ADP-ribose) polymerase (PARP) activation may be associated with Hhcy-induced endothelial dysfunction, which is an important mechanism for Hhcy to affect atherosclerotic progress. Thus, we investigated whether PARP inhibitors may attenuate atheroscle-rotic plaque development in an Hhcy-induced experimental animal model with atherosclerosis. METHODS: Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fed a normal diet or high methionine diet randomly received intraperitoneal injections of 10 mg/kg 3-aminoben-zamide (3-AB, a PARP inhibitor) dissolved in phosphate-buffered saline (PBS), or physiological saline every other day for 12 weeks. Atherosclerotic lesion sizes and PARP activity were measured. Related inflammatory factors in atherogenesis were investigated by real-time quantitative PCR and Western blot analysis. RESULTS: Our data demonstrated that ApoE-/- mice fed a high methionine diet generated Hhcy, which subsequently increased the atherosclerotic lesion size significantly, promoted oxidative stress-associated DNA damage and PARP activation, then increased the expression of proinflammatory fac-tors within atherosclerotic plaques. Although PARP inhibition by 3-AB did not markedly inhibit plaque development in ApoE-/- mice with spontaneous hyperlipidemia by feeding a normal diet, it significantly reduced the atherosclerotic lesion size by 40% in Hhcy-induced atherosclerosis without affecting plasma homocysteine levels and lipid contents, effectively suppressed PARP activation, and inhibited nuclear translocation of nuclear factor-(kappa)B (NF-(kappa)B) and subsequent production of inflam-matory factors, such as vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattactant protein-1 (MCP-1). CONCLUSION: Our results suggest that PARP inhibition attenuates atherosclerotic plaque development under hyperhomocysteinemic conditions, through the inhibition of PARP activation, nuclear NF-kappaB translocation and subsequent expression of inflammatory factors.

Atorvastatin modulates Th1/Th2 response in patients with chronic heart failure.

BACKGROUND: The T-helper (Th)1/Th2 imbalance has been demonstrated to be involved in chronic heart failure (CHF). We sought to determine whether atorvastatin exhibited any effect on CHF through modulating the Th1/Th2 response. METHODS AND RESULTS: We measured serum concentrations of interleukin (IL)-12, -18, interferon (IFN)-gamma, IL-4, and IL-10 from 20 controls and 72 patients with nonischemic CHF by enzyme-linked immunosorbent assay. To investigate the effect of atorvastatin in vivo, CHF patients were either classified into a usual therapy group (n = 35) or usual therapy plus atorvastatin (10 mg/day) group (n = 37). Patient serum levels of IFN-gamma and IL-4 were measured at time of admission and 2 weeks after treatment. Peripheral blood mononuclear cells from patients of CHF group were cultured in the presence or absence of atorvastatin (0, 0.4, 1, and 4 micromol/L) in vitro, and IFN-gamma and IL-4 levels were detected. Serum levels of IL-12, IL-18, and IFN-gamma were significantly higher in the CHF group than in the control group. The levels of IFN-gamma and the ratios of IFN-gamma:IL-4 were significantly decreased with atorvastatin treatment both in vivo and in vitro, whereas levels of IL-4 did not differ significantly. CONCLUSIONS: Th1 polarization exists in patients with CHF, and atorvastatin can modulate the Th1/Th2 response through inhibiting Th1 cytokine production.

Poly (ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by hyperhomocysteinemia in rats.

INTRODUCTION: We investigated the possible protective effect of poly (ADP-ribose) polymerase (PARP) inhibition in preventing endothelial dysfunction induced by hyperhomocysteinemia (Hhcy). METHODS: Sprague-Dawley rats were divided into Hhcy group, Hhcy + 3-aminobenzamide(3-AB) group, control group and control + 3-AB group. A high-methionine diet was given to induce hyperhomocysteinemia. In Hhcy + 3-AB and control + 3-AB groups, rats were injected intraperitoneally with 3-AB (inhibitor of PARP). After 45 days, ultrastructural changes of aortas were observed by transmission electron microscope. Vascular reactivity of thoracic aortic rings was measured in organ chambers. PARP activity was detected. The levels of plasma total homocysteine, nitrite/nitrate, endothelin (ET)-1 and malondialdehyde were assayed. RESULTS: Rats in Hhcy group developed severe hyperhomocysteinemia and significant loss of endothelial function as measured by both vascular rings and levels of nitrite/nitrate and ET-1. Malondialdehyde levels increased significantly in Hhcy rats compared with control rats. 3-AB improved Ach-induced, NO-mediated vascular relaxation and stabilized the level of nitrite/nitrate and ET-1. Obvious improvement of ultrastructure can be observed in Hhcy + 3-AB group. CONCLUSIONS: These results suggest that pharmacological inhibition of PARP prevents the development of endothelial dysfunction in rats with hyperhomocysteinemia which may represent a novel approach to improve vascular dysfunction associated with hyperhomocysteinemia.

Rapamycin modulates the maturation of rat bone marrow-derived dendritic cells.

The purpose of the study was to observe the effect of rapamycin (RAPA) on the differentiation and maturation of rat bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs from Wistar rats were cultured with granulocyte-macrophage colony-stimulating factor plus interleukin-4 in the presence or absence of RAPA (20 ng/mL), and stimulated with lipopolysaccharide (LPS) for 24 h before cells and supernatants were collected. Surface phenotype of BMDCs was flow-cytometrically detected to determine the expression of maturation markers, MHC class II and CD86. Supernatants were analyzed for the production of IL-12 and IFN-gamma cytokines by using ELISA. BMDCs were co-cultured with T cells from Lewis rats and mixed lymphocyte reaction was assessed by MTT method. The morphology of BMDCs stimulated with LPS remained immature after RAPA pretreatment. RAPA significantly decreased the CD86 expression, impaired the IL-12 and IFN-gamma production of BMDCs stimulated with LPS, and inhibited the proliferation of allogeneic T cells. In conclusion, RAPA can inhibit the maturation of BMDCs stimulated with LPS in terms of the morphology, surface phenotype, cytokine production, and ability of BMDCs to stimulate the proliferation of allogeneic T cells in vitro.

Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE(-/-) mice through modulation of Th1/Th2 balance.

Atherosclerosis is a chronic inflammatory disease, which is positively and negatively regulated by T helper (Th) 1 and Th2 lymphocytes, respectively. Recent findings indicate that suppressive oligodeoxynucleotides (ODNs) expressing TTAGGG motifs selectively reduce Th1 cytokine production and have been proven effective at blocking the development of organ-specific autoimmune diseases. In the current research, we hypothesized that suppressive ODNs may alter the development of atherosclerosis. Eight-week-old homozygous ApoE(-/-) male mice were injected with 300 mug ODNs A151 (TTAGGG) or nonspecific ODNs 1612. Atherosclerotic lesion sizes were dramatically reduced by ODNs A151, but not by nonspecific ODNs. MCP-1 and VCAM-1, which are the key inflammatory factors in atherogenesis, were significantly attenuated by the suppressive ODNs A151. In the splenic lymphocytes, FACS analysis showed ODNs A151 reduced the percentage of IFN-gamma-producing Th1 cells and slightly increased the percentage of IL-4-producing Th2 cells, indicating that suppressive ODNs skewed the Th1/Th2 balance toward Th2 inflammation in vivo. Furthermore, ODNs A151 down-regulated the phosphorylation of STAT1 and STAT4 and suppressed up-regulation of T-bet, a signal modulator for Th1, and didn't impact GATA-3 and STAT6, which are associated with a Th2 phenotype. Consistent with this in vivo observation, ELISA analysis demonstrated that ODNs A151 suppressed Th1 cytokines IFN-gamma and TNF-alpha, and augmented Th2 cytokines IL-4 and IL-10 in vitro. This study provides the first experimental evidence that suppressive ODNs inhibit the development of atherosclerosis through inhibition of the STAT1/4 and T-bet pathways, which further modulate the Th1/Th2 balance in vivo.

The Th17/Treg imbalance in patients with acute coronary syndrome.

Atherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets. Recently, CD4+CD25+Foxp3+ regulatory T (Treg) cells and Th17 cells have been described as two distinct subsets from Th1 and Th2 cells and have the opposite effects on autoimmunity. Th17/Treg balance controls inflammation and may be important in the pathogenesis of plaque destabilization and the onset of acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)]. To assess whether this balance was broken in patients with coronary heart disease, we detected Th17/Treg functions on different levels including cell frequencies, related cytokine secretion and key transcription factors in patients with AMI, UA, stable angina (SA) and controls. The results demonstrated that patients with ACS revealed significant increase in peripheral Th17 number, Th17 related cytokines (IL-17, IL-6 and IL-23) and transcription factor (RORgammat) levels and obvious decrease in Treg number, Treg related cytokines (IL-10 and TGF-beta1) and transcription factor (Foxp3) levels as compared with patients with SA and controls. Results indicate that Th17/Treg functional imbalance exists in patients with ACS, suggesting a potential role for Th17/Treg imbalance in plaque destabilization and the onset of ACS.

Molecular mechanisms of felodipine suppressing atherosclerosis in high-cholesterol-diet apolipoprotein E-knockout mice.

Oxidative stress and inflammation processes are key components of atherosclerosis, from fatty streak formation to plaque rupture and thrombosis. Evidence has revealed that calcium-channel blockers (CCB) could retard atherogenesis, but the exact mechanisms have not been fully elucidated. The present study was undertaken to investigate the potential effects and molecular mechanisms of the CCB felodipine on the process of atherosclerosis in high-cholesterol-diet (HCD) apolipoprotein E-knockout (ApoE KO) mice. Adult male ApoE KO mice were given a normal diet (ND) or HCD and were randomized to no treatment or felodipine (5 mg / kg per day for 12 weeks). The ApoE KO mice with HCD were associated with a marked increase in plasma lipid levels, atherosclerotic lesion area, and the expressions of NADPH oxidase subunits (p47 and Rac-1), nuclear factor-kappaB (NF-kappaB) in nucleus, phosphor-inhibitors of kappaB (p-IkappaB), tumor necrosis-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and vascular cell-adhesion molecule-1 (VCAM-1). These changes were suppressed in mice that were treated with felodipine (5 mg/kg per day for 12 weeks) concomitant with HCD administration, with no significant change in systolic blood pressure and plasma lipid levels. The results suggest that felodipine can attenuate atherosclerosis, and this effect is partly related to inhibition of oxidative stress and inflammatory signal-transduction pathways, which lead to decreases in the expression of inflammatory cytokines.

Rapamycin Modulates the Maturation of Rat Bone Marrow-derived Dendritic Cells / 华中科技大学学报（医学）（英德文版）

The purpose of the study was to observe the effect of rapamycin (RAPA) on the differentiation and maturation of rat bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs from Wistar rats were cultured with granulocyte-macrophage colony-stimulating factor plus interleukin-4in the presence or absence of RAPA (20 ng/mL), and stimulated with lipopolysaccharide (LPS) for 24h before cells and supernatants were collected. Surface phenotype of BMDCs was flow-cytometrically detected to determine the expression of maturation markers, MHC class Ⅱ and CD86. Supematants were analyzed for the production of IL-12 and IFN-γ cytokines by using ELISA.BMDCs were co-cultured with T cells from Lewis rats and mixed lymphocyte reaction was assessed by MTT method. The morphology of BMDCs stimulated with LPS remained immature after RAPA pretreatment. RAPA significantly decreased the CD86 expression, impaired the IL-12 and IFN-γproduction of BMDCs stimulated with LPS, and inhibited the proliferation of allogeneic T cells. In conclusion, RAPA can inhibit the maturation of BMDCs stimulated with LPS in terms of the morphology, surface phenotype, cytokine production, and ability of BMDCs to stimulate the proliferation of allogeneic T cells in vitro.