ADAM10 inhibits the interaction between IL-17 and HMGB1 in Buerger's disease.

OBJECTIVE: Buerger's disease is a rare disease that causes critical limb ischemia; however, the underlying pathophysiological mechanism remains unclear. Therefore, we investigated the interaction between interleukin (IL)-17 and high-mobility group protein B 1 (HMGB1) and determined whether A disintegrin and metalloproteinase 10 (ADAM10) inhibit this interaction. PATIENTS AND METHODS: The study population included 15 patients with Buerger's disease and 10 healthy donors without a history of giving peripheral blood samples. Cytokine levels were measured using a luminex multiplex assay in plasma. Flow cytometry was used to analyze the subtypes of helper T (Th) cells among peripheral blood mononuclear cells (PBMCs). The effect of ADAM10 on PBMCs was analyzed in vitro. RESULTS: The levels of inflammatory cytokines and production of pathogenic Th cells were found to be higher in Korean patients with Buerger's disease. IL-17 treatment induced HMGB1 associated molecules. HMGB1 also induced IL-17 and Th17 associated transcription factors in Buerger's patients. We observed that ADAM10 regulates the interaction between IL-17 and HMGB1 via advanced glycation end products (RAGE)/nuclear factor-kappa B (NF-kB) pathway in patients with Buerger's disease. CONCLUSIONS: This study suggests that IL-17 and HMGB1 cytokines contribute to the pathogenesis of Buerger's disease. These results indicate that ADAM10 alleviates inflammation in Buerger's disease via the HMGB1 and RAGE/NF-κB signaling pathway and provides insights into the molecular basis of and a potential therapeutic strategy for Buerger's disease.

Association of hypertension with small, dense low-density lipoprotein in patients without metabolic syndrome.

A higher proportion of small, dense low-density lipoprotein (sdLDL) is known to be associated with a high prevalence of cardiovascular disease in association with metabolic syndrome (MS). Hypertension (HTN) is one of the known risk factors for MS. However, whether HTN is associated with sdLDL in patients without MS is not yet clear. The lipid profiles, including low-density-lipoprotein (LDL) subfractions, of 383 consecutive subjects were evaluated. The patients without MS consisted of 198 hypertensive patients (non-MS/HTN group) and 108 normotensive subjects (non-MS/non-HTN group). The peak and mean particle diameter of LDL were measured by gradient gel electrophoresis. Plasma total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride (TG), HDL cholesterol/Apo A1, LDL-C/ApoB and Apo(A1, B, CII and E) levels did not differ between the non-MS/non-HTN and non-MS/HTN groups. When analyzing LDL subfraction, the absolute amount of patterns A and B was not different between the non-MS/non-HTN and non-MS/HTN groups. Compared with the non-MS/non-HTN groups, the proportion of sdLDL was higher in the non-MS/HTN group (37.7% versus 39.9%, P=0.046), but not significant after adjustment of waist circumference, serum TG, age and statin usage. The proportion of sdLDL to total LDL was higher in hypertensive subjects, even those without MS, than in normotensive subjects. However, this difference of LDL subfraction in hypertensive patients is associated with higher waist circumference, higher serum TG, older age and more statin usage. This result suggests that HTN may contribute to atherosclerosis and endothelial dysfunction with associated risk factors that influence LDL size.

Impact of hypertension on coronary artery spasm as assessed with intracoronary acetylcholine provocation test.

Both hypertension and coronary artery spasm (CAS) are associated with endothelial dysfunction. Thus, a higher incidence of CAS is expected in hypertensive patients. We evaluated the impact of hypertension on CAS with intracoronary acetylcholine (ACh) provocation test. A total of 986 patients (685 hypertensive patients vs 301 normotensive patients) who underwent coronary angiography with ACh provocation test were enrolled. ACh was injected into the left coronary artery in incremental doses of 20, 50 and 100 microg min(-1). Significant CAS was defined as a transient >70% luminal narrowing with concurrent chest pain and/or ST-segment changes. Although the incidences of significant ACh-induced CAS were similar between hypertensive and normotensive patients (35.8 vs 39.2%, P=0.303), multivariate logistic analysis showed that hypertension was negatively associated with ACh-induced CAS (odds ratio: 0.70, 95% confidence interval: 0.51-0.94, P=0.020). The angiographic characteristics of ACh-induced CAS were similar between these two groups. Subgroup analysis regarding the impact of the status of blood pressure control on CAS showed that hypertensive patients with controlled blood pressure had a significantly higher incidence of CAS than those with uncontrolled blood pressure (45.2 vs 27.9%, P<0.001), and that uncontrolled blood pressure was negatively associated with ACh-induced CAS (odds ratio: 0.56, 95% confidence interval: 0.40-0.79, P=0.001). In conclusion, despite the expected endothelial dysfunction, hypertension and uncontrolled blood pressure are negatively associated with CAS, suggesting that the mechanisms and risk factors of CAS may be significantly different from those of coronary artery disease.

Myocardial bridging is related to endothelial dysfunction but not to plaque as assessed by intracoronary ultrasound.

BACKGROUND: Myocardial bridge (MB) is characterised by focal compression of a coronary artery in systole by an overlying band of myocardium. Chronic compression and relaxation of the MB may produce endothelial dysfunction by direct stress. OBJECTIVE: To determine whether MB alters endothelial function, thus influencing the plaque formation. METHODS: 128 patients (mean (SD) age 54.7 (10.9) years, 56 men) with typical angiographic systolic milking effects and >30% reduction in diameter of the coronary artery during systole after intracoronary nitrate (glyceryl trinitrate, 200 mug) infusion were studied. 231 control patients (mean (SD) age 52.9 (12.1) years, 111 men) without overt coronary artery disease including MB were also studied. Endothelial function was estimated by incremental acetylcholine (Ach) infusion into the left coronary ostium. Intracoronary ultrasound assessments were obtained in 74/128 patients with MB and 81/231 controls. RESULTS: The mean (SD) vasoconstrictive response to maximal Ach was more pronounced at the bridging segments than at matched segments in controls (-71.9 (14.9) vs -30.3 (22.6), p = 0.009). Coronary vasoconstriction (>50%) to Ach was seen more often in the MB group than in controls (114/128 (89.1%) vs 81/231 (35.1%), p = 0.007). No significant correlation was found between the severity of MB and vasoconstriction in response to Ach. A typical half-moon phenomenon was seen in 71/74 (95.9%) cases of the MB group, but not in controls (p<0.001). Plaques at the bridging segments were absent in 67/74 (90.5%) and mild in 7/74 (9.5%) cases, as compared with those of matched segments of the left anterior descending coronary artery in controls (plaque burden 5.91 (1.37)% vs 24.71 (24.21)%, p = 0.002). CONCLUSION: Despite the prominent relationship between MB and endothelial dysfunction, bridging segments are spared from atherosclerotic plaque formation.

Relationship between blood pressure parameters and pulse wave velocity in normotensive and hypertensive subjects: invasive study.

Blood pressure (BP) is one of the most important contributing factors to pulse wave velocity (PWV), a classic measure of arterial stiffness. Although there have been many non-invasive studies to show the relation between arterial stiffness and BP, the results are controversial. The aim of this study is to evaluate the role of BP as an influencing factor on PWV using invasive method. We observed 174 normotensive and untreated hypertensive subjects using coronary angiography. Arterial stiffness was assessed through aorto-femoral PWV by foot-to-foot velocity method using fluid-filled system. And BP was measured by pressure wave at the right common femoral artery. From univariate analysis, age, diabetes mellitus (DM), hypertension, waist, waist-to-hip ratio, total cholesterol-to-high-density lipoprotein cholesterol ratio, systolic BP (SBP), pulse pressure (PP) and mean arterial pressure (MAP) showed significant association with PWV. To avoid multiple colinearity among SBP, PP and MAP, we performed multiple regression analysis predicting PWV thrice. Age, DM and each BP were significantly and consistently correlated to PWV. In the first and third modules, compared to age, SBP and MAP were less strong predictors, respectively. However, PP was the stronger predictor than age and DM in the second module. Lastly, we simultaneously forced MAP and PP with other variables in the fourth multivariate analysis. Age, DM and PP remained significantly correlated with PWV, but the significance of MAP was lost. This is the first invasive study to suggest that PP has the strongest correlation with PWV among a variety of BP parameters.