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ABSTRACT: Cardiovascular disease is a major cause of morbidity and mortality worldwide. Epidemiological studies have clearly demonstrated that chronic psychosocial stress increases the risk of atherosclerotic cardiovascular disease, and this may involve multiple mediators and regulating pathways, while the precise mechanisms underlying the effects of stress on development of atherosclerosis are not completely understood. In this mini-review, we summarize current information from various animal studies suggesting that stress may promote atherogenesis by stimulating vascular inflammation via elevating the level of circulating proinflammatory cytokines (such as tumor necrosis factor-α and interleukin-6). While circulating cytokines can serve as reliable biomarkers of systemic inflammation, in light of the emerging evidence we propose that these molecules may also have a causal role in mediating stress-triggered vascular inflammatory reaction and atherogenesis. Further studies are warranted to clarify whether targeting circulating cytokines may be an effective approach to reduce the detrimental effects of chronic stress.
Journal of cardiovascular pharmacology 01/2013; · 2.83 Impact Factor
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ABSTRACT: Endothelial progenitor cells (EPCs) can be used to repair tissues after myocardial infarction (MI) but EPC activators have adverse reactions. Rehmannia glutinosa is a herb used in traditional Chinese medicine, which can promote bone-marrow proliferation and protect the ischemic myocardium. We investigated the effects of Rehmannia glutinosa extract (RGE) on EPCs in a rat model of MI.
A total of 120 male Wistar rats were randomized to 2 groups (n = 60 each) for treatment: high-dose RGE (1.5 g·kg(-1)·day(-1) orally) for 8 weeks, then left anterior descending coronary artery ligation, mock surgery or no treatment, then RGE orally for 4 weeks; or normal saline (NS) as the above protocol. The infarct region of the left ventricle was assessed by serial sectioning and morphology. EPCs were evaluated by number and function. Protein and mRNA levels of CD133, vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-X-C motif receptor 4 (CXCR4), stromal cell-derived factor-1α (SDF-1α) were measured by immunohistochemistry, Western blot and quantitative PCR analysis.
RGE significantly improved left ventricular function, decreased the ischemic area and the apoptotic index in the infarct myocardium, also decreased the concentration of serum cardiac troponin T and brain natriuretic peptide at the chronic stage after MI (from week 2 to week 4). RGE increased EPC number, proliferation, migration and tube-formation capacity. It was able to up-regulate the expression of angiogenesis-associated ligand/receptor, including CD133, VEGFR2 and SDF-1α/CXCR4. In vitro, the effect of RGE on SDF-1α/CXCR4 cascade was reversed by the CXCR4 specific antagonist AMD3100.
RGE may enhance the mobilization, migration and therapeutic angiogenesis of EPCs after MI by activating the SDF-1α/CXCR4 cascade.
PLoS ONE 01/2013; 8(1):e54303. · 4.09 Impact Factor
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ABSTRACT: Chronic psychological stress is associated with an increased risk of atherosclerosis in humans. Experimental studies using various stress models have yielded controversial results. This study investigated the effects of unpredictable chronic mild stress (UCMS) on atherogenesis in New Zealand white rabbits.
Rabbits were fed with a cholesterol-enriched (1%) diet for 4 to 16 weeks, with or without concomitant UCMS treatment. Atherosclerosis was assessed in the abdominal aorta by serial sectioning and morphological analysis. Expressions of inflammatory factors were measured with immunohistochemistry and quantitative polymerase chain reaction. Serum nitrate/nitrite levels were determined with Griess assay, and corticosterone and inflammatory markers were determined using enzyme-linked immunosorbent assay.
High-cholesterol feeding resulted in hypercholesterolemia and formation of atherosclerotic plaques in the aorta. UCMS exposure significantly increased the plaque size (p = .003) and decreased the plaque stability (decreased the contents of collagen and smooth muscle and increased the amount of macrophage and matrix metalloproteinases). The proatherogenic effects of UCMS were unrelated to changes in serum cholesterol level but accompanied by increased blood pressure (p < .001) and vascular inflammation (up-regulation of tumor necrosis factor α, C-reactive protein, and monocyte chemoattractant protein 1, all p values < .01). Serum concentrations of nitrate/nitrite were lower in UCMS-treated animals (p = .01). Vessels from UCMS-treated animals exhibited augmented phosphorylation of p38 and c-Jun N-terminal kinase and activation of nuclear factor κB.
Chronic psychological stress may contribute to the development of atherosclerosis by enhancing vascular inflammation and decreasing endothelial nitric oxide bioavailability.
Psychosomatic Medicine 06/2012; 74(6):604-11. · 3.97 Impact Factor
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Jing Jing Li,
Xiao Meng,
Hai Peng Si,
Cheng Zhang,
Hui Xia Lv, Yu Xia Zhao,
Jian Min Yang,
Mei Dong,
Kai Zhang,
Su Xia Liu,
Xue Qiang Zhao,
Fei Gao,
Xiao Ling Liu,
Tai Xing Cui,
Yun Zhang
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ABSTRACT: To explore a direct and causal relationship between vascular hepcidin and atherosclerotic plaque stability.
Accelerated atherosclerotic lesions were established by perivascular collar placement in apolipoprotein E-deficient (ApoE(-/-)) mice. Adenoviral overexpression of hepcidin in the carotid artery during plaque formation enhanced intraplaque macrophage infiltration and suppressed the contents of collagen and vascular smooth muscle cells, whereas hepcidin shRNA treatment exerts opposite effects. The overexpression or knockdown of hepcidin did not affect plaque lipid deposition but increased or decreased oxidized low-density lipoprotein (ox-LDL) levels within intraplaque macrophages. In cultured macrophages, ox-LDL not only increased reactive oxygen species formation, inflammatory cytokine production, and apoptosis but also upregulated hepcidin expression. However, hepcidin did not exaggerate the ox-LDL-induced activation of macrophages until an onset of erythrophagocytosis. Whereas hepcidin was critical for the upregulation of L-ferritin and H-ferritin in both ox-LDL-treated erythrophagocytosed macrophages and atherosclerotic plaques, the adding of iron chelators suppressed the intracellular lipid accumulation, reactive oxygen species formation, inflammatory cytokine expression, and apoptosis in erythrophagocytosed macrophages.
Hepcidin promotes plaque destabilization partly by exaggerating inflammatory cytokine release, intracellular lipid accumulation, oxidative stress, and apoptosis in the macrophages with iron retention.
Arteriosclerosis Thrombosis and Vascular Biology 03/2012; 32(5):1158-66. · 6.37 Impact Factor
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Mei Dong,
Lin Zhong,
Wen Qiang Chen,
Xiao Ping Ji,
Mei Zhang, Yu Xia Zhao,
Li Li,
Gui Hua Yao,
Peng Fei Zhang,
Cheng Zhang,
Lei Zhang,
Yun Zhang
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ABSTRACT: Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels.
PLoS ONE 01/2012; 7(6):e39695. · 4.09 Impact Factor
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ABSTRACT: Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine (CCL2), has been demonstrated to play important roles in atherosclerosis and becoming an important therapeutic target for atherosclerosis. The present study was undertaken to test the hypothesis that local RNAi of MCP-1 by site-specific delivery of adenovirus-mediated small hairpin RNA (shRNA) may enhance plaque stability and prevent plaque disruption in ApoE-/- mice. We designed an adenovirus-mediated shRNA against mouse MCP-1 (rAd5-MCP-1-shRNA). Male apolipoprotein E-knockout (ApoE-/-) mice (n = 120) were fed a high-fat diet and vulnerable plaques were induced by perivascular placement of constrictive collars around the carotid artery, intraperitoneal injection of lipopolysaccharide and stress stimulation. Mice were randomly divided into RNA interference (Ad-MCP-1i) group receiving local treatment of rAd5-MCP-1-shRNA suspension, Ad-EGFP group receiving treatment of rAd5-mediated negative shRNA and mock group receiving treatment of saline. Two weeks after treatment, plaque disruption rates were significantly lower in the Ad-MCP-1i group than in the Ad-EGFP group (13.3% vs. 60.0%, P = 0.01), and local MCP-1 expression was significantly inhibited in the Ad-MCP-1i group confirmed by immunostaining, qRT-PCR and western blot (P<0.001). Compared with the Ad-EGFP group, carotid plaques in the Ad-MCP-1i group showed increased levels of collagen and smooth muscle cells, and decreased levels of lipid and macrophages. The expression of inflammatory cytokines and activities of matrix metalloproteinases (MMPs) were lower in the Ad-MCP-1i group than in the Ad-EGFP group. In conclusion, site-specific delivery of adenoviral-mediated shRNA targeting mouse MCP-1 downregulated MCP-1 expression, turned a vulnerable plaque into a more stable plaque phenotype and prevented plaque disruption. A marked suppression of the local inflammatory cytokine expression may be the central mechanism involved.
PLoS ONE 01/2012; 7(3):e33497. · 4.09 Impact Factor
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Juan Wang,
Feng Shuang An,
Wei Zhang,
Lei Gong,
Shu Jian Wei,
Wei Dong Qin,
Xu Ping Wang, Yu Xia Zhao,
Yun Zhang,
Cheng Zhang,
Ming-Xiang Zhang
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ABSTRACT: Atherosclerosis begins as local inflammation of arterial walls at sites of disturbed flow, such as vessel curvatures and bifurcations with low shear stress. c-Jun NH₂-terminal kinase (JNK) is a major regulator of flow-dependent gene expression in endothelial cells in atherosclerosis. However, little is known about the in vivo role of JNK in low shear stress in atherosclerosis. We aimed to observe the effect of JNK on low shear stress-induced atherogenesis in apolipoprotein E-deficient (ApoE(-/-)) mice and investigate the potential mechanism in human umbilical vein endothelial cells (HUVECs). We divided 84 male ApoE(-/-) mice into two groups for treatment with normal saline (NS) (n = 42) and JNK inhibitor SP600125 (JNK-I) (n = 42). Perivascular shear stress modifiers were placed around the right carotid arteries, and plaque formation was studied at low shear stress regions. The left carotid arteries without modifiers represented undisturbed shear stress as a control. The NS group showed atherosclerotic lesions in arterial regions with low shear stress, whereas the JNK-I group showed almost no atherosclerotic lesions. Corresponding to the expression of proatherogenic vascular cell adhesion molecule 1 (VCAM-1), phospho-JNK (p-JNK) level was higher in low shear stress regions with NS than with JNK-I inhibitor. In HUVECs under low shear stress, siRNA knockdown and SP600125 inhibition of JNK attenuated nuclear factor (NF)-κB activity and VCAM-1 expression. Furthermore, siRNA knockdown of platelet endothelial cell adhesion molecule 1 (PECAM-1) (CD31) reduced p-JNK and VCAM-1 levels after low shear stress stimulation. JNK may play a critical role in low shear stress-induced atherogenesis by a PECAM-1-dependent mechanosensory pathway and modulating NF-κB activity and VCAM-1 expression.
Molecular Medicine 05/2011; 17(9-10):990-9. · 3.76 Impact Factor
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Xue Qiang Zhao,
Ming Wei Zhang,
Fei Wang, Yu Xia Zhao,
Jing Jing Li,
Xu Ping Wang,
Pei Li Bu,
Jian Min Yang,
Xiao Ling Liu,
Ming Xiang Zhang,
Fei Gao,
Cheng Zhang,
Yun Zhang
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ABSTRACT: Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. We hypothesized that the inflammatory marker C-reactive protein (CRP) might stimulate sLOX-1 release by activating tumor necrosis factor-α converting enzyme (TACE). Macrophages differentiated from THP-1 cells were stimulated with TNF-α and further treated with CRP in the absence or presence of specific inhibitors or small interfering RNA (siRNA). Our results showed that CRP increased sLOX-1 release from activated macrophages in a dose-dependent manner and that these effects were regulated by Fc γ receptor II (FcγRII)-mediated p47(phox) phosphorylation, reactive oxygen species (ROS) production, and TACE activation. CRP also enhanced sLOX-1 release from macrophages derived from peripheral blood mononuclear cells (PBMC) of patients with acute coronary syndrome (ACS). Pretreatment with antibody against FcγRII or with CD32 siRNA, p47(phox) siRNA, apocynin, N-acetylcysteine, tumor necrosis factor-α protease inhibitor 1 (TAPI-1) or TACE siRNA attenuated sLOX-1 release induced by CRP. CRP also elevated serum sLOX-1 levels in a rabbit model of atherosclerosis. Thus, CRP might stimulate sLOX-1 release, and the underlying mechanisms possibly involved FcγRII-mediated p47(phox) phosphorylation, ROS production, and TACE activation.
The Journal of Lipid Research 03/2011; 52(5):923-33. · 5.56 Impact Factor
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Yu Xia Zhao,
Hui Qiu Yin,
Qing Tao Yu,
Yun Qiao,
Hong Yan Dai,
Ming Xiang Zhang,
Lei Zhang,
Yun Fang Liu,
Lai Cheng Wang,
De Shan Liu, [......],
Yue Hui Zhang,
Chun Ming Pan,
Huai Dong Song,
Xun Qu,
Hong Jiang,
Chun Xi Liu,
Xiao Ting Lu,
Bin Liu,
Fei Gao,
Bo Dong
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ABSTRACT: The purpose of this study was to test the hypothesis that overexpression of angiotensin-converting enzyme 2 (ACE2) may favorably affect left ventricular (LV) remodeling and function after myocardial infarction (MI). The left anterior descending coronary artery was ligated to produce anterior MI in 100 Wistar-Kyoto rats that were randomly divided into Ad-ACE2, Ad-ACE2+A779, Ad-EGFP, model, and sham groups. Two weeks later, rats in the Ad-ACE2 and Ad-EGFP groups received direct intramyocardial injection of Ad-ACE2 and Ad-EGFP, respectively. Rats in the Ad-ACE2+A779 group received both intramyocardial injection of Ad-ACE2 and a continuous intravenous infusion of A779 for 15 days. LV volume and systolic function, the extent of myocardial fibrosis, and levels of ACE2, angiotensin II (Ang II), and collagen I protein expression were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed reduced LV volume, extent of myocardial fibrosis, and expression levels of ACE, Ang II, and collagen I in the myocardium, and increased LV ejection fraction and levels of ACE2 activity and expression in comparison with the Ad-EGFP and model groups. These results suggest that ACE2 overexpression attenuated LV fibrosis and improved LV remodeling and systolic function. In conclusion, overexpression of ACE2 favorably affected the pathological process of LV remodeling after MI by inhibiting ACE activity, reducing AngII levels, and up-regulating Ang-(1-7) expression, thus providing a potential therapeutic target in the treatment of heart failure.
Human gene therapy 11/2010; 21(11):1545-54. · 4.20 Impact Factor
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ABSTRACT: To examine whether danshensu could protect vascular endothelia in a rat model of hyperhomocysteinemia.
The model was established by feeding rats with a methionine-rich diet (1 g·kg⁻¹·d⁻¹) for 3 months. Immediately following the discontinuation of methionine-rich diet, rats were treated with danshensu (67.5 mg·kg⁻¹·d⁻¹, po) or saline for 3 additional months. One group of rats receiving vitamin mixture (folic acid, vitamin B12 and vitamin B6) was included as a positive control. One group of rats not exposed to methionine-rich diet was also included as a blank control. The expression of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) protein in the descending aorta was examined using immunohistochemistry and Western blot. Homocysteine and blood concentration of endothelin and nitric oxide (NO) was also examined.
Methionine-rich diet resulted in accumulation of "foam cells", up-regulated expression of TNF-alpha and ICAM-1 in the descending aorta, and significantly increased serum homocysteine. Plasma endothelin concentration was significantly increased; NO was decreased. Danshensu treatment, either simultaneous to methionine-rich diet or afterwards, attenuated the above mentioned changes.
Chronic treatment with danshensu could prevent/attenuate the formation of atherosclerosis. Potential mechanisms include inhibited expression of representative proinflammatory cytokines and adhesion molecules in arterial endothelia. Changes in homocysteine and circulating molecules that control vascular contraction/relaxation via endothelial cells (eg, endothelin and NO) were also implicated.
Acta Pharmacologica Sinica 10/2010; 31(10):1395-400. · 1.95 Impact Factor
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ABSTRACT: Adventitial fibroblasts (AFs) and inflammation play an important role in neointimal formation and vascular remodeling. The present study was aimed to investigate the therapeutic effects and underlying mechanisms of transcriptional regulator Gax gene transfection in aortic remodeling induced by adventitial inflammation.
Fifty rabbits fed a chow diet were randomly divided into a normal control group (n=10) and experimental group (n=40). All rabbits in the experimental group underwent collar placement around the abdominal aorta and intra-collar injection of lipopolysaccharide (LPS) to induce adventitial inflammation and they were further divided into model control group, saline-treated group, green fluorescence protein (Ad-GFP)-treated group and Gax gene (Ad-Gax)-treated group, respectively. Four weeks after treatment, the model control group, saline-treated group and Ad-GFP-treated group showed thickened neointima and adventitia, reduced lumen size and increased eccentricity and remodeling index of the abdominal aorta in comparison with the normal control group, whereas Ad-Gax-treated group exhibited attenuated neointimal formation and vascular remodeling (P<0.01-0.05) .The vascular expression levels of interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, Smads, mitogen-activated protein kinases (MAPKs), integrins and nuclear factor kappa B (NF-kB) were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those in the normal control group (P<0.01-0.05). In contrast, the local expression levels of these cytokines were substantially reduced by Ad-Gax gene transfer (P<0.01-0.05). Similarly, the serum levels of inflammatory cytokines including C-reactive protein (CRP), transforming growth factor (TGF)-β1, IL-1, IL-6, IL-8, tumor necrosis factor (TNF)-α, MCP-1, VCAM-1 and ICAM-1 were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those of the Ad-Gax-treated group (P<0.01-0.05). In vitro studies showed that Gax overexpression diminished inflammatory cytokine expression in LPS-stimulated arterial fibroblasts.
Adventitial inflammation induces vascular remodeling via the interactions of multiple inflammatory cytokines and local Gax gene transfer in vivo can significantly inhibit these interactions and thereby attenuate local inflammation and vascular remodeling.
Atherosclerosis 10/2010; 212(2):398-405. · 3.79 Impact Factor
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Cheng Zhang, Yu Xia Zhao,
Yue Hui Zhang,
Li Zhu,
Bi Ping Deng,
Zhao Li Zhou,
Shu Ying Li,
Xiao Ting Lu,
Li Li Song,
Xue Ming Lei,
Wen Bo Tang,
Nan Wang,
Chun Ming Pan,
Huai Dong Song,
Chun Xi Liu,
Bo Dong,
Yun Zhang,
Yihai Cao
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ABSTRACT: Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERK-p38, JAK-STAT, and AngII-ROS-NF-kappaB signaling pathways and up-regulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.
Proceedings of the National Academy of Sciences 09/2010; 107(36):15886-91. · 9.68 Impact Factor
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been reported to play important roles in the modulation of anxiety, mood stabilizers, and pathophysiology of affective disorders. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (Val66Met) has been found to be associated with depression and anxiety disorders. The humanized BDNF(Met/Met) knock-in transgenic mice exhibited increased anxiety-related behaviors that were unresponsive to serotonin reuptake inhibitors, fluoxetine. Music is known to be able to elicit emotional changes, including anxiolytic effects. In this study, we found that music treatment could significantly decrease anxiety state in BDNF(Met/Met) mice, but not in BDNF(+/)(-), mice compared with white noise exposure in open field and elevated plus maze test. Moreover, in contrast to white noise exposure, BDNF expression levels in the prefrontal cortex (PFC), amygdala and hippocampus were significantly increased in music-exposed adult BDNF(Met/Met) mice. However, music treatment could not upregulate BDNF levels in the PFC, amygdala, and hippocampus in BDNF(+/)(-) mice, which suggests the essential role of BDNF in the anxiolytic effect of music. Together, our results imply that music may provide an effective therapeutic intervention for anxiety disorders in humans with this genetic BDNF(Met) variant.
Brain research 08/2010; 1347:71-9. · 2.46 Impact Factor
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ABSTRACT: To evaluate the reliability of velocity vector imaging (VVI) for detecting vulnerable plaques.
After aortic balloon injury, 60 rabbits were fed a 1% cholesterol diet for 10 weeks and normal chow for another 6 weeks. Adenovirus containing p53 or lac Z was then injected into the aortic plaques and rabbits were divided into p53-treated group (n=20), lac Z-treated group (n=20) and blank control group (n=20). Peak longitudinal (LSp), radial (RSp) and circumferential (CSp) strain of plaques was measured using VVI at the end of week 18 before pharmacological triggering. Higher RSp and CSp and lower LSp were found in ruptured than those in non-ruptured plaques, and RSp, CSp and LSp correlated well with the fibrous cap thickness and plaque content of macrophages, smooth muscle cells and collagen (all p<0.01). A logistic regression model showed that both RSp (RR: 8.96, 95% CI: 5.3575-10.4857, p<0.001) and CSp (RR: 8.45, 95% CI: 5.9043-9.1043, p<0.001) were significant predictors of plaque rupture. RSp and CSp had a sensitivity of 88.0% and 88.6% and a specificity of 88.6% and 92.0% to predict plaque disruption, respectively.
VVI offers a new and noninvasive technique for measuring the peak strain of atherosclerotic plaques and RSp and CSp are a novel index with a high sensitivity and specificity for detecting plaques vulnerable to rupture.
Atherosclerosis 01/2010; 211(1):146-52. · 3.79 Impact Factor
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Lei Zhang,
Yan Liu,
Xiao Ting Lu,
Yi Ling Wu,
Cheng Zhang,
Xiao Ping Ji,
Rong Wang,
Chun Xi Liu,
Jin Bo Feng,
Hong Jiang,
Xin Sheng Xu, Yu Xia Zhao,
Yun Zhang
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ABSTRACT: This study was carried out to test the hypothesis that Tongxinluo (TXL) as a Chinese herbal medicine enhances stability of vulnerable plaque dose dependently via lipid-lowering and anti-inflammation effects, similar to a high-dose simvastatin therapy. After abdominal aortic balloon injury, 75 rabbits were fed a 1% cholesterol diet for 10 wk and were then divided into five groups for 8-wk treatment: control group, low-dose TXL group, moderate-dose TXL group, high-dose TXL group, and high-dose simvastatin group. At the end of week 16, an adenovirus containing p53 was injected into the abdominal aortic plaques. Two weeks later, plaque rupture was induced by pharmacological triggering. The incidence of plaque rupture in all treatment groups (14.3%, 7.1%, 7.7%, and 7.1%) was significantly lower than that in control group (73.3%; P>0.01). TXL dose-dependently lowered serum lipid levels and inhibited systemic inflammation. Corrected acoustic intensity and fibrous cap thickness of the aortic plaques were significantly increased, whereas plaque area, plaque burden, vulnerable index, and expression of oxidized low-density lipoprotein (ox-LDL) receptor 1, matrix metalloproteinase 1 (MMP-1), MMP-3, tissue inhibitor of MMP 1, and NF-kappaB in plaques were markedly reduced in all treatment groups when compared with the control group. Similar to high-dose simvastatin group, high-dose TXL group exhibited a low serum level of low-density lipoprotein cholesterol and ox-LDL, a low expression level of systemic and local inflammatory factors and a low plaque vulnerability index, with no differences in the incidence of plaque rupture among all treatment groups. TXL dose-dependently enhances the stability of vulnerable plaques and prevents plaques from rupture. Simvastatin and TXL offer similar protection in terms of lipid-lowering, anti-inflammation, and antioxidation effects.
AJP Heart and Circulatory Physiology 10/2009; 297(6):H2004-14. · 3.71 Impact Factor
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ABSTRACT: RELEVANCE TO ETHNOPHARMACOLOGY: Tongxinluo capsule is a compound preparation formulated on the basis of the meridian theory of traditional Chinese medicine and is officially approved for the treatment of angina pectoris and ischemic stroke in China.
To test the hypothesis that the Chinese traditional medicine tongxinluo in capsule form has similar effects as simvastatin in lowering serum lipid levels and stabilizing vulnerable plaques.
Thirty New Zealand white rabbits underwent balloon-induced abdominal aortic endothelial injury and were fed a diet of 1% cholesterol for 8 weeks. The rabbits were then randomly divided into three groups (n=10 each) for daily doses of tongxinluo capsule (1 g/kg), simvastatin (5 mg/kg) or no drugs for 12 weeks. At the end of week 20, plaque rupture was induced by pharmacological triggering. Serological, ultrasonographic, pathologic, immunohistochemical, and gene expression studies were performed.
The incidence of plaque rupture with tongxinluo and simvastatin treatment was significantly lower than that with control treatment (0% for both drug treatments vs. 56.0%; P<0.05). Values of serum lipid profile, inflammatory markers, and pathological and immunohistological assays were significantly improved in the tongxinluo- and simvastatin-treated groups than in the control group. The simvastatin-treated group showed lower serum lipid levels than the tongxinluo-treated group.
Treatment with the Chinese medicine tongxinluo was as effective as simvastatin in lowering serum lipid levels, inhibiting plaque inflammation and preventing vulnerable plaques from rupture and may provide an alternative therapy for atherosclerosis.
Journal of ethnopharmacology 08/2009; 124(1):103-10. · 2.32 Impact Factor
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ABSTRACT: OBJECTIVE: To test the hypothesis that stimulation of chymase secretion may contribute to plaque vulnerability and inhibition of chymase activity may enhance plaque stability. METHODS AND RESULTS: Sixty eight-week-old male Syrian golden hamsters were randomly divided into normal control group, high-cholesterol (HC) treated group, HC+ovalbumin treated group and HC+tranilast treated group. The normal control group received a normal diet while the other three intervention groups received a high-cholesterol diet for 15 weeks. Hamsters in the HC+ovalbumin treated group underwent transcatheter pharmacological triggering at the end of week 15 after antigen sensitization and those in the HC+tranilast treated group were given tranilast intragastrically for 3 weeks before euthanasia. Serological, ultrasonographic, pathologic, immunohistochemical, and gene expression studies were performed in all animals. The total number of mast cells, proportion of degranulated mast cells and the number of extracellular granules in plaques, the apoptosis rate of vascular smooth cells, the local activities of chymase, the concentration of Ang II and the expression levels of inflammatory markers as well as plaque vulnerability index all increased significantly in HC+ovalbumin treated group, but remarkably decreased in HC+tranilast treated group, in comparison with the HC treated group. These results suggest that stimulation of chymase secretion contributes to plaque vulnerability while inhibition of chymase activity enhances plaque stability. We conclude that chymase activity provides a promising therapeutic target in the stabilization of atherosclerotic plaques.
Atherosclerosis 05/2009; 207(1):59-67. · 3.79 Impact Factor
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ABSTRACT: To establish an animal model with disruptions of atherosclerotic plaques, 96 male apolipoprotein E knockout (apoE(-/-)) mice were randomly divided into stress, lipopolysaccharide (LPS), stress+LPS, and control groups (n = 24 each). All mice were fed a high-fat diet throughout the experiment, and carotid atherosclerotic lesions were induced by placement of a constrictive perivascular collar. Four weeks after surgery, mice in the LPS and stress+LPS groups were intraperitoneally injected with LPS (1 mg/kg twice per week for 8 wk). Eight weeks after surgery, mice in the stress and stress+LPS groups were treated with intermittent physical stress (electric foot shock and noise stimulation) for 4 wk. Morphological analysis revealed a plaque disruption rate of 16.7% in control, 34.8% in LPS, 54.2% in stress, and 60.9% in stress+LPS groups. The disruption rates in stress and stress+LPS groups were both significantly higher than those of controls (P = 0.007 and P = 0.002, respectively). Luminal thrombosis secondary to plaque disruption was observed only in the stress+LPS group. Both stress and LPS stimulation significantly decreased fibrous cap thickness and increased macrophage and lipid contents in plaques. Moreover, the combination of stress and LPS stimulation further lowered cap thickness and enhanced accumulation of macrophages and expression of inflammatory cytokines and matrix metalloproteinases. Stress activated the sympathetic nervous system, as manifested by increased blood pressure and flow velocity. Plasma fibrinogen levels were remarkably elevated in the stress and stress+LPS groups. In conclusion, stress- and LPS-costimulated apoE(-/-) mice provide a useful model for studies of plaque vulnerability and interventions.
AJP Heart and Circulatory Physiology 04/2009; 296(5):H1598-606. · 3.71 Impact Factor
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ABSTRACT: Atherosclerotic plaque rupture and thrombosis are the main cause of acute coronary syndrome. The study was aimed to test the hypothesis that oral administration of rapamycin may attenuate inflammation, inhibit progression and enhance stability of atherosclerotic plaques.
Thirty New Zealand rabbits were subjected to balloon-induced endothelial injury of the abdominal aorta and were fed a diet of 1% cholesterol for 20 weeks. From week 9 to week 20, the animals were treated with oral rapamycin (0.5 mg x kg(-1) x day(-1); group A), oral simvastatin (5 mg x kg(-1) x day(-1); group B) and no drugs (group C). At the end of week 20, all rabbits were challenged with injection of Chinese Russell's viper venom and histamine. Serological, ultrasonographic, pathological, immunohistochemical and gene expression studies were performed.
Rapamycin significantly increased the thickness of the fibrous caps and decreased plaque vulnerability index in group A rabbits. Serum lipid levels were higher whereas plaque burden was lower in group A than in group B (P < 0.05). The incidence of plaque rupture in group A (0%) and group B (0%) was significantly lower than that in group C (56.0%, P < 0.05).
Oral administration of rapamycin effectively attenuated inflammation, inhibited progression and enhanced stability of atherosclerotic plaques in rabbits, without altering serum lipid levels. Our findings suggest a novel approach to the treatment of atherosclerosis.
British Journal of Pharmacology 03/2009; 156(6):941-51. · 4.41 Impact Factor
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Peng Fei Zhang,
Hai Jun Su,
Gui Hua Yao,
Wei Wu,
Mei Zhang,
Chun Xi Liu,
Hong Jiang,
Shi Fang Ding,
Cheng Zhang, Yu Xia Zhao,
Yun Zhang
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ABSTRACT: The purpose of this study was to develop a new biomechanical index for assessing the elastic characteristics of carotid plaques and to test the association between carotid plaque elasticity and ischemic cerebrovascular events (ICEs).
One hundred and eighteen carotid plaques were detected with real-time three-dimensional ultrasonography in 104 patients. All patients received MRI and were divided into two groups according to the history of ICEs: patients with ICEs (n=58, including 20 patients with transient ischemic attack and 38 with ischemic stroke) and patients without ICEs (n=46). The carotid plaque volume at end diastole (Vd) and end systole (Vs) was measured by use of a TomTec (Munich, Germany) workstation. Plaque volume compression ratio (VCR) was calculated as (Vd-Vs)/Vd x 100 and the reproducibility of VCR measurement was analyzed. The carotid intima-media thickness, plaque area and plaque acoustic density were also measured. Multivariate logistic regression was used to test the association between ICEs and plaque ultrasonic parameters or traditional risk factors including age, sex, smoking, blood pressure, history of coronary heart disease, levels of serum low-density lipoprotein, triglyceride and glucose.
Satisfactory images of carotid plaques were obtained in all patients by real-time three-dimensional ultrasonography. Patients with ICEs and patients without ICEs differed significantly in VCR (22.19+/-8.42 vs. 13.95+/-7.86, P<0.01). Regression analysis revealed that systolic blood pressure, [odds ratio (OR)=1.054, 95% confidence interval (CI)=1.028-1.081, P<0.001] and VCR (OR=1.074, 95% CI=1.022-1.128, P<0.001) were associated with ICEs independently. Plaque volume had only a marginal association with ICEs (OR=1.007, 95% CI=1.000-1.013, P=0.05).
Measurement of VCR provides a noninvasive approach to the evaluation of the elasticity of carotid plaques, which is associated independently with ICEs. Thus, real-time three-dimensional ultrasonography-derived VCR holds a great potential in identifying patients with high risk of ICEs.
Journal of Hypertension 02/2009; 27(2):348-56. · 4.02 Impact Factor
