The signaling and functions of the Endothelial Differentiation Gene (EDG) family of G protein-coupled receptors have been extensively elucidated. All the members of EDG family were shown to be receptors for lysosphingolipids or lysophospholipids. EDG-1, the prototype of EDG family receptors, is a high affinity receptor for serum-borne bioactive lipid, Sphingosine-1-phosphate (S1P). S1P, secreted by thrombotic platelets, has been shown to regulate a variety of cellular responses, including survival, cytoskeletal remodeling, chemotaxis etc, via the activation of cell surface EDG receptors. Recently, a novel function of S1P in modulating angiogenic response has been demonstrated. This review will focus on S1P/ EDG-1 signaling in endothelial activation, in particular in the S1P-mediated adherens junctions assembly and chemotaxis in endothelial cells.
Epidemiologic studies have provided support for the association between delayed remnant removal and premature atherosclerosis. Triglyceride-rich particles such as chylomicrons and chylomicron remnants that carry dietary derived fats, may play a role in the early stages of developing arteriosclerosis. Currently research focuses on these lipoprotein classes seeking distinguishing factors that causes some lipoproteins to be atherogenic while others are not. Such lipoproteins could be involved in atherogenesis directly or indirectly. Direct involvement occurs by interaction of triglyceride-rich particles with the arterial wall, possibly affecting the artery wall by oxidative stress, direct endothelial toxicity by constituents such as lysophosphatidylcholine or oxysterols, induction of prothrombotic changes, stimulation of endothelial expression of cell adhesion molecules and direct interaction with circulating blood cells. Indirect involvement refers to the influence of triglyceride-rich lipoproteins on other lipoproteins on the composition of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles. We propose that in individuals with delayed removal of chylomicron remnants, the prolonged exposure of areas of endothelium that have been partially activated by turbulent flow, to specific components of the remnants, results in the endothelial cells becoming further activated and able to bind monocytes. During or shortly after the transcytosis to the intima and transformation of monocytes to macrophages, the macrophages become engorged with remnant derived lipids and form the nidus of a fatty streak.
The mevalonate pathway plays a crucial role in regulation of cellular cholesterol synthesis and isoprenoid groups. The entire pathway is closely regulated by feedback from an enzyme in the cascade, 3-hydroxy-3-methyl-CoA (HMG-CoA) reductase, as well as LDL receptors. Clinically, inhibition of this pathway by statins, potent inhibitors of HMG-CoA reductase, has been shown to reduce plasma levels of LDL cholesterol and several clinical trials with this group of drugs have demonstrated a remarked improvement in cardiovascular risk reduction. Interestingly, the improvement in cardiovascular end points in those trials was superior to estimations calculated from the effect on LDL cholesterol lowering. These findings support the idea of non-lipid effects of statins in atherosclerosis. Further, recent observations using in vivo and in vitro models of atherosclerosis have shed light on their potential role for manipulation of various cellular functions via inhibition of the mevalonate pathway. Among them, recently identified inhibitory effects of statins on monocyte-endothelial interaction suggest their effect on inflammation. Herein, we discuss recent progress in this area of study, with special focus on the biological function of statins.
Background: Accurate and precise measurements of total cholesterol (TC) and HDL-cholesterol (HDL-C) are necessary for effective diagnosis and treatment of lipid disorders. We studied the impact of TC certification and HDL-C evaluation in Japanese clinical laboratories to standardize their measurements.
Methods: We selected 78 laboratories participated at least twice for TC and 46 laboratories participated twice for HDL-C in the standardization protocols developed by the Cholesterol Reference Method Laboratory Network (CRMLN). We compared the initial and subsequent results using the performance guidelines established by US National Cholesterol Education Program (NCEP).
Results: For TC, mean percentage bias of all participants was - 0.93% and - 0.49% for the initial and second rounds, respectively. Mean within-sample CV was 0.72% and 0.69% for the initial and second rounds, respectively. For HDL-C, mean percentage bias of all participants was - 1.86% and - 0.06% for the initial and second events, respectively. Mean among-run CV was 1.56% and 1.58% for the initial and second events, respectively.
Conclusions: TC accuracy in the second round than the initial round tended to improvement although statistically not significant, however in the five years follow-up, mean absolute percentage bias was reduced over time. HDL-C accuracy was statistically improved in the second event than the initial event. The precision for both TC and HDL-C did not change. This study shows CRMLN protocols contribute effectively to improvement of TC and HDL-C performance.
We investigated the relation between the serum concentration of HGF and carotid atherosclerosis. Serum concentrations of HGF were measured in 128 in-patients (mean age, 74 ± 11 years) free from cardiac, liver and renal diseases, in addition to lung diseases, in the Medical Department of Nomura Municipal Hospital between August, 2000 and June, 2001. Carotid intima-media thickness (IMT) was evaluated by ultrasonography with a 7.5 MHz linear type B-mode probe. The results showed a significantly positive correlation between serum age and HGF concentrations in patients with carotid atherosclerosis (IMT > 1.0 mm) (r = 0.391, p = 0.005). On the other hand, there was no significant correlation between age and serum HGF concentration in those without carotid atherosclerosis (IMT ≤ 1.0 mm) (r = 0.157, p = 0.173). A general linear model analysis for HGF adjusted with other risk factors showed that the age-carotid atherosclerosis interactions were significantly associated with serum HGF (F [1.114] = 6.193; p = 0.014), in addition to age, systolic blood pressure (SBP), aniti-hypertensive drug use, diabetes mellitus and carotid atherosclerosis. In contrast, multiple regression analysis showed that serum HGF (β = 0.160, p = 0.033) was independently associated with carotid atherosclerois, in addition to gender, age, SBP and HDL-cholesterol. These results suggest that increased serum HGF concentrations were associated with carotid atherosclerosis, independent of known risk factors for atherosclerosis.
Atorvastatin, a second generation synthetic 3-hydroxy 3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor used in the treatment of hypercholesterolemia, reduces both intracellular cholesterol synthesis and serum cholesterol levels, and this could have a potential negative impact on gonadal and adrenal steroidogenesis. Hypercholesterolemia in type 2 diabetes, even when mild, must be treated in an aggressive way, due to the more strict therapeutic goals than in the non diabetic population. Since the wide use of 3-hydroxy 3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor (statins) in type 2 diabetes, the main aim of our study was to evaluate the effects of “therapeutic” doses of atorvastatin on gonadal and adrenal hormones in 24 type 2 diabetic patients (16 males and 8 postmenopausal females), with mild to moderate hypercholesterolemia (LDL-cholesterol = 150.1 ± 32.0 and 189.9 ± 32.9 mg/dl, respectively) studied before and after a 3 months treatment with atorvastatin (20 mg/day). In all patients, lipids and serum cortisol, dehydroepiandrosterone sulphate (DHEA-S), androstendione and sex hormone binding globulin (SHBG) were measured, with the addition, only in males, of testosterone and free testosterone index. After atorvastatin treatment a significant decrease in total and LDL cholesterol was observed (p < 0.05), while HDL-cholesterol did not significantly change ( p = N.S.), as no significant difference was found between steroid hormones measured before and after atorvastatin either in male and females. In conclusion, our data suggest that, in type 2 diabetic patients, the use of atorvastatin has no clinically important effects on either gonadal or adrenal steroid hormones.
Low HDL-cholesterol (HDL-C) has long been used as an important predictor of coronary artery disease (CAD), although HDL-C values themselves are influenced by various factors including serum triglyceride (TG) levels, obesity, and life style. In view of the importance of the metabolic syndrome as a risk factor of CAD, changes in HDL-C and other lipid parameters in the Japanese population associated with life style, especially in males, were analyzed in this study based on data obtained in an epidemiological survey carried out in 1990. Smokers had higher TG and lower HDL-C levels than non-smokers, while BMI and LDL-C were slightly decreased by smoking in middle-aged men (40-59 years old). Increases in both HDL-C and TG due to alcohol consumption were associated with an increase in BMI in younger men aged 20-39. In middle-aged men, significant increases in HDL-C were seen in every quintile of BMI, while the increase in TG levels due to alcohol was small. Middle-aged men engaged in occupations requiring greater physical activity also had higher HDL-C levels in every quintile of BMI. The influence of life style on serum lipid parameters appeared to be mostly expressed as a function of BMI in younger men, while it appeared to be independent of BMI in older men.
The importance of metabolic syndrome as a risk factor of coronary artery disease (CAD) has recently become more and more recognized. In view of such a background, changes in cholesterol and other lipid parameters in the Japanese population associated with excess body weight and hypertension were analyzed in this study based on data obtained in an epidemiological survey carried out in 1990. Hypertension was closely associated with a higher body mass index (BMI). Among the lipid parameters, triglyceride (TG) and non-HDL-C (total cholesterol minus HDL-cholesterol) levels showed remarkable differences between hypertensive and normotensive subjects, with a greater statistical significance than LDL-cholesterol (LDL-C) levels. Changes in lipid parameters in the presence of hypertension were mostly associated with an increase in BMI in younger men aged 20-39, while increases in TG levels took place independently of excess body weight in middle-aged (40-59-year old) men. Considering that hypertension is a common and the greatest risk factor in the Japanese population, TG and non-HDL-C appear to be more important than LDL-C as major lipid parameters related to atherogenesis.
Small, dense low-density lipoprotein (LDL) is an atherogenic lipoprotein because of its susceptibility to oxidative modification. However, evaluating LDL size requires highly sophisticated techniques. We investigated potentially convenient biochemical parameters for assessing the presence of small, dense LDL. Thirty-nine male subjects, who had been involved in a work-site health promotion program, were recruited. Subjects were divided into two groups: normal LDL size (> 25.5 nm, Normal LDL group) and small LDL (≤ 25.5 nm, Small LDL group). Significant negative correlations were observed between LDL size and both triglyceride (TG) (p < 0.001) and remnant-like particle cholesterol concentrations (p < 0.01), while there was a significant positive correlation between LDL size and the high density lipoprotein cholesterol (HDL-C) concentration (p < 0.01). The TG concentration was a negative and the HDL-C concentration a positive independent variable predicting LDL size in multiple regression analysis (p < 0.0001). Seventy-five percent of the Small LDL group had TG/HDL-C ratios higher than 0.9 using mmol/L or 2.0 using mg/dL, while only 25% of the normal LDL group had ratios above the levels (p = 0.0013). A combined parameter, the TG/HDL-C ratio, is beneficial for assessing the presence of small LDL.
We report a patient with severe hypertriglyceridemia associated with anemia and hypoalbuminemia, in which the former may have caused the latter two conditions. This is the first reported case of abrupt onset of severe hypertriglyceridemia resulting in suppression of bone marrow and liver function.