Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration.

The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease. The aim of this study was to explore the role of Gas6/Axl system in high glucose (HG)-induced endothelial dysfunction.

Background and aim of the study: Rupture of the sinus of Valsalva is rare, and there is a higher incidence of such rupture in Oriental countries than elsewhere. The objective of this study is to present the pathologic features and the clinical outcome after surgery in such patients. Methods: Between 1980 and 2001, a total of 17 patients (15 males and 2 females) with ruptured aneurysm of sinus of Valsalva underwent surgical intervention at the Tri‐Service General Hospital, Taiwan. Their age ranged from 22 to 59 years with a mean of 33.5 years. These surgical operations made up 0.51% of the total cardiac operations (3305) performed during this period. The medical records were retrospectively reviewed. Results: The origin of the ruptured aneurysm of the sinus of Valsalva was the right coronary sinus in 12 patients, the noncoronary sinus in 4, and the left coronary sinus in one patient. The aneurysms ruptured into the right ventricle in 12 patients, into the right atrium in 3 patients, and into the left ventricle in 2 patients. Associated cardiac anomalies were aortic regurgitation in eight patients, ventricular septal defect in seven, and coronary artery fistula in one patient. There was no early postoperative death and one patient underwent a second operation after aneurysm of the sinus of Valsalva (ASV) relapse. Conclusions: The operation for a ruptured aneurysm of sinus of Valsalva carries a low operative risk and results in excellent long‐term survival after surgical treatment. (J Card Surg 2004;19:99‐102)

The tyrosine kinase receptor Axl is expressed in the vasculature, and growth arrest-specific protein 6 (Gas6) is its ligand. Plasma Gas6 levels have been shown to be associated with endothelial dysfunction markers and cardiovascular events. We set out to determine the plasma Gas6 levels in patients undergoing coronary artery bypass grafting (CABG) and investigate the expression of Gas6 and Axl in the aorta. Immunoassays were used to investigate plasma Gas6 levels in CABG patients (n = 19) and control subjects (n = 20). The expression of Gas6 and Axl in the injured aorta were examined by reverse transcription-polymerase chain reactions, real-time reverse transcription-polymerase chain reactions, western blotting, and immunohistochemical staining. Plasma Gas6 levels were significantly lower in CABG patients than in matched control subjects. In CABG patients, plasma Gas6 levels were negatively correlated with fasting glucose, E-selectin, and vascular cell adhesion molecule-1 levels. The levels predicted the operative mortality rate and were positively correlated with plasma soluble Axl (sAxl) levels and Gas6 expression in the aorta. Moreover, Gas6 expression was positively correlated with Axl expression in the aorta. We concluded that plasma Gas6 is associated with fasting glucose, endothelial dysfunction markers, sAxl values, and vascular Gas6 expression in CABG patients, and it predicts the operative mortality of these patients. These findings suggest that the Gas6/Axl system is crucial in vascular biology.