Atorvastatin Represses the Angiotensin 2-Induced Oxidative Stress and Inflammatory Response in Dendritic Cells via the PI3K/Akt/Nrf 2 Pathway

Dendritic cells (DCs), which are highly proficient antigen-presenting cells, play a complex role in both the initiation and progression of atherosclerosis. We tested the hypothesis that the anti-inflammatory and antioxidant effects of atorvastatin may be partly mediated by the phosphatidylinositol 3-kinase/protein kinase B/transcription factor nuclear factor-erythroid 2-related factor 2 (PI3K/Akt/Nrf 2) pathway via the attenuation of DC maturation, thus reducing the inflammatory and oxidative stress responses. This study showed that angiotensin 2 (Ang 2) induced the maturation of DCs, stimulated CD83, CD40, CD80, and CD86 expression, and increased the secretion of IL-12p70, IL-6, and TNF-α. These effects were suppressed by atorvastatin. Atorvastatin also lowered the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), counteracting their initial increases in response to Ang 2 stimulation. Atorvastatin activated Nrf 2 via the PI3K/Akt pathway and thereby promoted Nrf 2 translocation from the cytoplasm to the nucleus in bone marrow-derived dendritic cells (BMDCs), a process that was reversed by the PI3K inhibitor LY294002. Therefore, the regulation of Nrf 2 expression by the PI3K/Akt pathway plays an important role in the regulation of the statin-mediated antioxidant and anti-inflammatory responses in DCs

Impact of sphingomyelin levels on coronary heart disease and left ventricular systolic function in humans

Sphingomyelin (SM) is an abundant phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; therefore, higher levels of SM may promote atherogenesis. We investigated the relations between plasma SM levels and the presence of angiographic coronary heart disease (CHD) and left ventricular systolic dysfunction. We studied 732 patients referred for coronary angiography. Median SM levels were higher among patients with CHD and in those with LV systolic dysfunction (LVEF<50%) than in patients without CHD or LV dysfunction. SM levels were significantly correlated with fibrinogen levels, diabetes, apoB, and triglyceride levels. On multivariate analyses, higher median SM levels were associated with a higher risk of CHD and lower LV ejection fraction. The pro-atherogenic property of plasma SM might be related to 1) CHD; 2) LV systolic dysfunction; and 3) metabolism of apoB-containing or triglyceride-rich lipoproteins

Transfer of Bone-Marrow-Derived Mesenchymal Stem Cells Influences Vascular Remodeling and Calcification after Balloon Injury in Hyperlipidemic Rats

Bone-marrow-derived mesenchymal stem cells (BM-MSCs) were found to markedly increase atherosclerotic lesion size. The aim of this paper was to investigate whether BM-MSCs contribute to vascular remodeling and calcification after balloon injury in hyperlipidemic rats. Labeled BM-MSCs were found in the lesion of hyperlipidemic rats after balloon injury. Comparing injury group, transferred BM-MSCs significantly triggered vascular negative remodeling, characterized by the changes of remodeling index (0.628 ± 0.0293 versus 0.544 ± 0.0217), neointimal area (0.078 ± 0.015 mm2 versus 0.098 ± 0.019 mm2), PCNA index (23.91 ± 6.59% versus 43.11 ± 5.31%), and percentage of stenosis (18.20 ± 1.09% versus 30.58 ± 1.21%). Apparent vascular calcification was detected in medial layers at 6 weeks after balloon angioplasty, which may be associated with upregulation of bone morphogenetic protein-2 (BMP-2). Our data indicated that unselected BM-MSCs transfer may induce vascular remodeling and calcification after balloon injury in hyperlipidemic rats

Plasma PLTP activity is inversely associated with HDL-C levels

Phospholipid transfer protein (PLTP) is an important modulator of lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. PLTP also plays an important role in inflammation and oxidative stress. Accordingly, PLTP has been implicated in the development of atherosclerosis. In this study, we evaluated the association between PLTP activity and lipoprotein metabolism in a Chinese patients cohort with or without coronary heart disease (CHD group n = 407, control group n = 215), the PLTP activity was measured and PLTP genotyping was screened for sequence anomalies by PCR. We found that human plasma PLTP activity was negatively associated with plasma HDL and apoA-I levels, and positively associated with plasma TG, apoB and apoE levels. We also found that PLTP rs2294213 polymorphism was tended to be associated with increased plasma PLTP activity

Heat shock transcription factor 1 preserves cardiac angiogenesis and adaptation during pressure overload

To examine how heat shock transcription factor 1 (HSF1) protects against maladaptive hypertrophy during pressure overload, we subjected HSF1 transgenic (TG), knockout (KO) and wild type (WT) mice to a constriction of transverse aorta (TAC), and found that cardiac hypertrophy, functions and angiogenesis were well preserved in TG mice but were decreased in KO mice compared to WT ones at 4 weeks, which was related to HIF-1 and p53 expression. Inhibition of angiogenesis suppressed cardiac adaptation in TG mice while overexpression of angiogenesis factors improved maladaptive hypertrophy in KO mice. In vitro formation of vasculatures by microvascular endothelial cells was higher in TG mice but lower in KO mice than in WT ones. A siRNA of p53 but not a HIF-1 gene significantly reversed maladaptive hypertrophy in KO mice whereas a siRNA of HIF-1 but not a p53 gene induced maladaptive hypertrophy in TG mice. Heart microRNA analysis showed that miR-378 and miR-379 were differently changed among the three mice after TAC, and miR-378 or siRNA of miR-379 could maintain cardiac adaptation in WT mice. These results indicate that HSF1 preserves cardiac adaptation during pressure overload through p53-HIF-1-associated angiogenesis, which is controlled by miR-378 and miR-379

AngiotensinII Preconditioning Promotes Angiogenesis In Vitro via ERKs Phosphorylation

AngiotensinII (AngII) is involved in not only the formation of cardiac hypertrophy but also the development of cardiac remodeling both of which are associated with myocardial angiogenesis. This study was therefore performed to clarify the effects of AngII on the formation of vasculatures by cultured cardiac microvascular endothelial cells (CMVECs) after a long-period stimulation with or without the AngII preconditioning. Incubation with AngII for 18 hrs significantly impaired the formation of capillary-like tubes comparing to that without AngII. CMVECs with AngII pretreatment for 5 and 10 min formed more capillary-like tubes than those without AngII pretreatment, suggesting that preconditioning with AngII at a lower dose for a short period could prevent the further damage of CMVECs by a higher concentration of AngII. Moreover, AngII (10−7 M) stimulation for 5 and 10 min significantly induced the increase in extracellular signal-regulated protein kinases (ERKs) phosphorylation, and an ERKs inhibitor, PD98059, abrogated the increase in the formation of capillary-like tubes induced by the AngII-pretreatment. In conclusion, preconditioning with a lower concentration of AngII for a short period prevents the subsequent impairment of CMVECs by a higher dose of AngII, at least in part, through the increase in ERKs phosphorylation

Changes of dendritic cells and fractalkine in type 2 diabetic patients with unstable angina pectoris: a preliminary report

<p>Abstract</p> <p>Background</p> <p>It has been shown that dendritic cells (DCs) and fractalkine play a role in accelerating progression of the inflamed atherosclerotic lesions and plaque rupture. We evaluated the numbers and functional changes of DCs and its subsets in human type 2 diabetes with or without unstable angina pectoris (UAP).</p> <p>Methods</p> <p>The study population consisted of 39 diabetic patients (DM:18 without CAD; DM + UAP: 21 with UAP), 18 non-diabetic UAP patients (UAP), and 15 healthy control (Normal). Peripheral blood DCs and its subsets were measured by three color flow cytometry. Serum levels of fractalkine, IL-12, and IFN-α were also measured. The functional status of the monocyte-derived DCs was analyzed by flow cytometry and allogeneic mixed T lymphocytes reaction.</p> <p>Results</p> <p>The percent and absolute numbers of DCs and mDC within the total leukocyte population was similar for Normal and DM, while significantly lower in DM + UAP. pDC numbers were not significantly altered. Serum fractalkine in DM + UAP was highest among the four groups (<it>p </it>= 0.04 vs. UAP, <it>p </it>= 0.0003 vs. DM, <it>p </it>< 0.0001 vs. Normal). Circulating mDC inversely correlated with serum fractalkine (r = -0.268, <it>p </it>= 0.01) level. Compared with DM and UAP, the costimulatory molecules CD86 and proliferation of T cells stimulated by DCs were significantly increased in DM + UAP group.</p> <p>Conclusions</p> <p>Our study suggested that increases in the fractalkine level and the number and functional changes of blood DCs might contribute to diabetic coronary atherosclerosis and plaque destabilization.</p