Regulatory T Cell Immunity in Atherosclerosis

Atherosclerosis is a chronic inflammatory disorder involving innate and adaptive immunity process. Effector T cell (Teff) responses promote atherosclerotic disease, whereas regulatory T cells (Tregs) have been shown to play a protective role against atherosclerosis by down-regulating inflammatory responses which include multiple mechanisms. Compelling experimental data suggest that shifting the Treg/Teff balance toward Tregs may be a possible therapeutic approach for atherosclerotic disease, although the role of Tregs in human atherosclerotic disease has not been fully elucidated. In this review, we discuss recent advances in our understanding of the roles of Tregs and Teffs in experimental atherosclerosis, as well as human coronary artery disease

Practical aspects of Kelvin-probe force microscopy at solid/liquid interfaces in various liquid media

The distributions of surface charges or surface potentials on biological molecules and electrodes are directly related to various biological functions and ionic adsorptions, respectively. Electrostatic force microscopy and Kelvin-probe force microscopy (KFM) are useful scanning probe techniques that can map local surface charges and potentials. Here, we report the measurement and analysis of the electrostatic and capacitive forces on the cantilever tip induced by application of an alternating voltage in order to discuss the feasibility of measuring the surface charge or potential distribution at solid/liquid interfaces in various liquid media. The results presented here suggest that a nanometer-scale surface charge or potential measurement by the conventional voltage modulation techniques is only possible under ambient conditions and in a non-polar medium and is difficult in an aqueous solution. Practically, the electrostatic force versus dc voltage curve in water does not include the minimum, which is used for the surface potential compensation. This is because the cantilever oscillation induced by the electrostatic force acting on the tip apex is overwhelmed by the parasitic oscillation induced by the electrostatic force acting on the entire cantilever as well as the surface stress effect. We both experimentally and theoretically discuss the factors which cause difficulties in application of the voltage modulation techniques in the aqueous solutions and present some criteria for local surface charge and potential measurements by circumventing these problems

The Role of S1P2 in Atherogenesis

Aim: The bioactive lipid, sphingosine-1-phosphate (S1P), has various roles in the physiology and pathophysiology of many diseases. There are five S1P receptors; however, the role of each S1P receptor in atherogenesis is still obscure. Here we investigated the contribution of S1P receptor 2 (S1P2) to atherogenesis by using a specific S1P2 antagonist, ONO-5430514, in apolipoprotein E-deficient (Apoe−/− ) mice. Methods: Apoe−/− mice fed with a western-type diet (WTD) received ONO-5430514 (30 mg/kg/day) or vehicle. To examine the effect on atherogenesis, Sudan IV staining, histological analysis, qPCR, and vascular reactivity assay was performed. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. Results: WTD-fed Apoe−/− mice had significantly higher S1P2 expression in the aorta compared with wild-type mice. S1P2 antagonist treatment for 20 weeks reduced atherosclerotic lesion development (p＜0.05). S1P2 antagonist treatment for 8 weeks ameliorated endothelial dysfunction (p＜0.05) accompanied with significant reduction of lipid deposition, macrophage accumulation, and inflammatory molecule expression in the aorta compared with vehicle. S1P2 antagonist attenuated the phosphorylation of JNK in the abdominal aorta compared with vehicle (p＜0.05). In HUVEC, S1P promoted inflammatory molecule expression such as MCP-1 and VCAM-1 (p＜0.001), which was attenuated by S1P2 antagonist or a JNK inhibitor (p＜0.01). S1P2 antagonist also inhibited S1P-induced JNK phosphorylation in HUVEC (p＜0.05). Conclusions: Our results suggested that an S1P2 antagonist attenuates endothelial dysfunction and prevents atherogenesis. S1P2, which promotes inflammatory activation of endothelial cells, might be a therapeutic target for atherosclerosis

Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure

SummaryObjectivesThis study was designed to determine the prognostic importance of left ventricular (LV) myocardial stiffness, a hemodynamic index which is closely related to B-type natriuretic peptide (BNP) concentration in patients with congestive heart failure (CHF).BackgroundWhile elevated BNP, an abnormality of cardiac neurohormones, is known to be an independent marker of death or re-admission, it remains to be clarified whether there is also a strong predictor directly related to cardiac dysfunction.MethodsLV performance variables and stress–strain analyses including diastolic myocardial stiffness constant (Km) were obtained from 37 patients with initial CHF by the combined simultaneous measurement of echocardiographic and hemodynamic data. Survivors were monitored for a mean of 23 months, with the main endpoint being combined death or first re-admission for CHF.ResultsTen patients (27%) were primary endpoint cases. Both Km and plasma BNP levels were higher in the event than in the event-free group. By Cox proportional hazards analysis, Km≥4.0 was identified as the only variable with significant and independently incremental predictive power to affect the primary endpoint (adjusted hazard ratio=7.354, 95% confidence interval 1.379–39.232, p=0.02).ConclusionsIn patients with CHF, increased myocardial stiffness may have greater prognostic significance compared to other conventional predictors. Increased myocardial stiffness may be considered to be an important prognostic factor independent of the loading conditions

Impact of hemodialysis on local vessel healing and thrombus formation after drug-eluting stent implantation

AbstractBackgroundAlthough hemodialysis (HD) is a suggested risk factor for stent thrombosis, its contribution to local vessel healing after drug-eluting stent (DES) implantation is unclear.MethodsA total of 121 patients (152 lesions treated with DES) who underwent 8-month follow-up coronary angiography with optical coherence tomography (OCT) were enrolled, and the findings were compared between patients with and without HD. To match baseline differences, mid-term OCT findings of 42 propensity score-matched lesions (21 non-HD vs. 21 HD) were compared. Effects of HD on the efficacy of antiplatelet therapy were also evaluated by VerifyNow assay (Accumetrics, San Diego, CA, USA).ResultsPatients with HD had a significantly higher rate of thrombus formation than those without (64% vs. 33%, p=0.007), although the baseline parameters and lesion characteristics differed between the groups. Multivariate logistic regression analysis revealed that HD was associated with an increased risk of thrombus formation (odds ratio 5.991, 95% confidence interval: 1.972–18.199, p=0.002). Even after propensity-matching for patient background and balancing of angiographic and OCT variables, the risk of thrombus formation remained significantly higher in HD patients. The P2Y12-reaction unit was significantly increased after HD (Pre HD: 211±75 vs. Post HD: 262±59, p=0.01), but patients without HD showed no increase during the same elapsed time (221±88 vs. 212±96, p=0.19).ConclusionsHD is a potential risk factor for subclinical thrombus attachment after DES therapy. Systemic problems, such as residual platelet reactivity, associated with HD as well as local vessel features in HD patients might contribute to the increased incidence of thrombus attachment and subsequent onset of thrombotic event after DES implantation

Family with Sequence Similarity 5, Member C (FAM5C) Increases Leukocyte Adhesion Molecules in Vascular Endothelial Cells: Implication in Vascular Inflammation

Identification of the regulators of vascular inflammation is important if we are to understand the molecular mechanisms leading to atherosclerosis and consequent ischemic heart disease, including acute myocardial infarction. Gene polymorphisms in family with sequence similarity 5, member C (FAM5C) are associated with an increased risk of acute myocardial infarction, but little is known about the function of this gene product in blood vessels. Here, we report that the regulation of the expression and function of FAM5C in endothelial cells. We show here that FAM5C is expressed in endothelial cells in vitro and in vivo. Immunofluorescence microscopy showed localization of FAM5C in the Golgi in cultured human endothelial cells. Immunohistochemistry on serial sections of human coronary artery showed that FAM5C-positive endothelium expressed intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). In cultured human endothelial cells, the overexpression of FAM5C increased the reactive oxygen species (ROS) production, nuclear factor-κB (NF-κB) activity and the expression of ICAM-1, VCAM-1 and E-selectin mRNAs, resulting in enhanced monocyte adhesion. FAM5C was upregulated in response to inflammatory stimuli, such as TNF-α, in an NF-κB- and JNK-dependent manner. Knockdown of FAM5C by small interfering RNA inhibited the increase in the TNF-α-induced production of ROS, NF-κB activity and expression of these leukocyte adhesion molecule mRNAs, resulting in reduced monocyte adhesion. These results suggest that in endothelial cells, when FAM5C is upregulated in response to inflammatory stimuli, it increases the expression of leukocyte adhesion molecules by increasing ROS production and NF-κB activity

Topographic variability of the left atrium and pulmonary veins assessed by 3D-CT predicts the recurrence of atrial fibrillation after catheter ablation

AbstractBackgroundCatheter ablation (CA) is an established therapy for atrial fibrillation (AF). However, the assessment of anatomical information and predictors of AF recurrence remain unclear. We investigated the relationship between anatomical information on the left atrium (LA) and pulmonary veins (PVs) from three-dimensional computed tomography images and the recurrence of AF after CA.MethodsSixty-seven consecutive AF patients (mean age: 62±10 years, median AF history: 42 (12; 60) months, mean LA size: 41±7mm, paroxysmal: 56%) underwent CA and were followed for 19±10 months. The segmented surface areas (antral, posterior, septal, and lateral) and dimensions (between the anterior and posterior walls, the right inferior PV and mitral annulus [MA], the right superior PV and MA, the left superior PV and MA, and the mitral isthmus) of the LA were evaluated three dimensionally using the NavX system. The cross-sectional areas of the PVs were also evaluated.ResultsAfter the follow-up period, 49 patients (73%) remained free from AF. A multivariate analysis showed that the diameter of the mitral isthmus and cross-sectional area of the right upper PV were associated with AF recurrence (odds ratio: 1.070, CI: 1.02–1.12, p=0.001; odds ratio: 0.41, CI: 0.21–0.77, p=0.006).ConclusionEnlargement of the mitral isthmus and a smaller right superior PV cross-sectional area were associated with AF recurrence

Geochemical characteristics of back-arc basin lower crust and upper mantle at final spreading stage of Shikoku Basin: an example of Mado Megamullion

AbstractThis paper explores the evolutional process of back-arc basin (BAB) magma system at final spreading stage of extinct BAB, Shikoku Basin (Philippine Sea) and assesses its tectonic evolution using a newly discovered oceanic core complex, the Mado Megamullion. Bulk and in-situ chemical compositions together with in-situ Pb isotope composition of dolerite, oxide gabbro, gabbro, olivine gabbro, dunite, and peridotite are presented. Compositional ranges and trends of the igneous and peridotitic rocks from the Mado Megamullion are similar to those from the slow- to ultraslow-spreading mid-ocean ridges (MOR). Since the timing of the Mado Megamullion exhumation corresponds to the very end of the Shikoku Basin opening, the magma supply was subdued and highly episodic, leading to extreme magma differentiation to form ferrobasaltic, hydrous magmas. In-situ Pb isotope composition of magmatic brown amphibole in the oxide gabbro is identical to that of depleted source mantle for mid-ocean ridge basalt (MORB). In the context of hydrous BAB magma genesis, the magmatic water was derived solely from the MORB source mantle. The distance from the back-arc spreading center to the arc front increased away through maturing of the Shikoku Basin to cause MORB-like magmatism. After the exhumation of Mado Megamullion along detachment faults, dolerite dikes intruded as a post-spreading magmatism. The final magmatism along with post-spreading Kinan Seamount Chain volcanism were introduced around the extinct back-arc spreading center after the opening of Shikoku Basin by residual mantle upwelling