Lipoprotein subfraction profile and HDL-associated enzymes in sickle cell disease patients.

Although hypocholesterolemia is a reported finding in sickle cell disease (SCD), low-density lipoprotein (LDL)/high-density lipoprotein (HDL) subfractions and HDL-associated enzymes have not been determined in SCD patients. Blood was collected from 38 hemoglobin (Hb)A volunteers and 45 homozygous HbSS patients who had not received blood transfusions in the last 3 months. Serum lipids were measured by automated analyzer while LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis. Serum levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels were significantly decreased, while TG levels were significantly increased in SCD patients compared to controls. A significant decrease in intermediate-density lipoprotein (IDL)-C, IDL-B, IDL-A and LDL-1 fractions were seen in SCD patients, while no significant difference was observed in small dense LDL particles. A significant decrease was seen in HDL-large, HDL-intermediate and HDL-small fractions in SCD patients versus controls. Levels of LCAT and ApoA-1 protein measured in SCD patients were significantly lower while no significant difference was observed in CETP and ApoB protein levels compared to controls. The reduction observed in LDL- and HDL-C in SCD patients was reflected as significantly decreased IDL, LDL-1 and HDL-subfractions. Decreased HDL subfractions may possibly lead to the reduced ApoA-1 and LCAT protein levels observed in SCD patients.

Usefulness of monocyte chemoattractant protein-1 to predict no-reflow and three-year mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Although monocyte chemoattractant protein-1 (MCP-1) levels are increased in patients with ST-segment elevation myocardial infarction, the prognostic value of MCP-1 in primary percutaneous coronary intervention (pPCI) is not clear. The goal of the present study was to investigate the association of MCP-1 levels with myocardial perfusion and prognosis in patients with ST-segment elevation myocardial infarction undergoing pPCI. Consecutive pPCI patients (n = 192) were assigned to tertiles according to their admission serum MCP-1 levels. Angiographic no-reflow, Thrombolysis In Myocardial Infarction flow grade, myocardial blush grade, and ST-segment resolution were assessed. Mortality and major adverse cardiac events were evaluated during hospitalization and at the 3-year clinical follow-up visit. Failure of ST resolution was associated with greater admission MCP-1 levels. The risk of no-reflow (Thrombolysis In Myocardial Infarction flow ≤2 or Thrombolysis In Myocardial Infarction flow 3 with final myocardial blush grade ≤2 after pPCI and ST resolution <30%) increased as the admission MCP-1 increased. The 3-year mortality increased as the MCP-1 level increased (8% vs 22% vs 28% for the 3 tertiles, p <0.01). Multivariate logistic regression analysis demonstrated that MCP-1 levels at admission are a significant independent correlate of 3-year mortality in patients with no-reflow as detected by myocardial blush grade. A receiver operating characteristics analysis identified an optimum cut point of ≥254 pg/ml, which was associated with a negative predictive value of 95% in association with 1-year mortality. In conclusion, the plasma MCP-1 levels at admission are independently associated with the development of no-reflow and 3-year mortality in patients with ST-segment elevation myocardial infarction undergoing pPCI.

Gas6-axl receptor signaling is regulated by glucose in vascular smooth muscle cells.

OBJECTIVE: The receptor tyrosine kinase Axl and its ligand Gas6 are involved in the development of renal diabetic disease. In vascular smooth muscle cells (VSMCs) Axl is activated by reactive oxygen species and stimulates migration and cell survival, suggesting a role for Axl in the vascular complications of diabetes. METHODS AND RESULTS: We investigated the effect of varying glucose concentration on Axl signaling in VSMCs. Glucose exerted powerful effects on Gas6-Axl signaling with greater activation of Akt and mTOR in low glucose, and greater activation of ERK1/2 in high glucose. Plasma membrane distribution and tyrosine phosphorylation of Axl were not affected by glucose. However, coimmunoprecipitation studies demonstrated that glucose changed the interaction of Axl with its binding partners. Specifically, binding of Axl to the p85 subunit of PI3-kinase was increased in low glucose, whereas binding to SHP-2 was increased in high glucose. Furthermore, Gas6-Axl induced migration was increased in high glucose, whereas Gas6-Axl mediated inhibition of apoptosis was greater in low glucose. CONCLUSIONS: This study demonstrates a role for glucose in altering Axl signaling through coupling to binding partners and suggests a mechanism by which Axl contributes to VSMC dysfunction in diabetes.