i(3)so3-galactosylceramide and Cardiovascular-Diseases

Sulfatides are sphingolipids commonly found at the surface of most of eukaryotic cells. Sulfatides are not just structural components of the plasma membrane but also participate in a wide range of cellular processes including protein trafficking, cell adhesion and aggregation, axon-myelin interactions, neural plasticity, and immune responses, among others. The intriguing question is how can sulfatides trigger such cellular processes? Their dynamic presence and specific localization at plasma membrane sites may explain their multitasking role. Crystal and NMR structural studies have provided the basis for understanding the mechanism of binding by sulfatide-interacting proteins. These proteins generally exhibit a hydrophobic cavity that is responsible for the interaction with the sulfatide acyl chain, whereas the hydrophilic, negatively charged moiety can be found either buried in the hydrophobic cavity of the protein or exposed for additional intermolecular associations. Since sulfatides vary in their acyl chain composition, which are tissue-dependent, more emphasis on understanding acyl chain specificity by sulfatide-binding proteins is warranted. Importantly, changes in cellular sulfatide levels as well as circulating sulfatides in serum directly impact cardiovascular and cancer disease development and progress. Therefore, sulfatides might prove useful as novel biomarkers. The scope of this review is to overview cell functions and mechanisms of sulfatide recognition to better understand the role of these lipids in health and disease.

Topics: Animals; Autoimmunity; Cardiovascular Diseases; Carrier Proteins; Host-Pathogen Interactions; Humans; Immunity, Innate; Neoplasms; Platelet Adhesiveness; Platelet Aggregation; Sulfoglycosphingolipids

Sulfatides are major glycosphingolipids of lipoproteins that influence atherosclerosis and blood coagulation. Our previous cross-sectional study of hemodialysis patients showed that serum sulfatide levels decreased markedly with increasing duration of hemodialysis treatment, which may contribute to the development of cardiovascular disease. However, this past study could not demonstrate the time-dependent change in serum sulfatide levels in each patient, and the underlying mechanism is unknown. To confirm the time-dependent aggravation of serum sulfatide abnormality, 95 stable hemodialysis outpatients were followed up for 3 years. To show the underlying mechanisms, we statistically analyzed correlations between serum sulfatide levels and clinical factors, including an oxidative stress marker, malondialdehyde. Serum sulfatides were quantified by mass spectrometry after conversion to lysosulfatides. Malondialdehyde was measured using a colorimetric assay. The results showed a time-dependent decrease in serum sulfatide levels associated with increased malondialdehyde levels, although the absolute level of serum malondialdehyde does not determine the baseline level of serum sulfatides. Multiple linear regression analysis showed a significant correlation only between the time-dependent change in serum sulfatide levels and the time-dependent change in serum malondialdehyde levels. This study demonstrated, for the first time, a time-dependent aggravation of serum sulfatide abnormality in hemodialysis patients, as well as the potential relationship between serum sulfatide abnormality and increasing oxidative stress. These findings suggest that oxidative stress might be an aggravating factor in serum sulfatide abnormality. As continuation of hemodialysis treatment hardly improves abnormal serum sulfatide levels or increased oxidative stress, development of novel therapeutic strategies may be important.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Oxidative Stress; Renal Dialysis; Sulfoglycosphingolipids

Oxidative stress (OS) is a strong risk factor for cardiovascular disease (CVD). The incidence of CVD is lower among kidney transplantation (KT) recipients than hemodialysis patients, and the reduction in OS may be one reason for this difference. Recently, serum sulfatides were recognized as a candidate inhibitory factor of CVD affected by OS. However, the long-term changes in OS and serum sulfatide levels in KT recipients are unknown.. We investigated the long-term changes in a serum OS marker, malondialdehyde (MDA), and the serum sulfatide levels in 17 KT recipients. Multiple regression analysis was used to analyze the factors correlated with serum sulfatide levels.. The high serum levels of MDA in the KT recipients decreased dramatically but were still high 1 year after KT surgery. MDA levels decreased further and reached near-normal levels more than 3 years after the surgery. Similarly, over the same 3 years, the low serum sulfatide levels increased to near-normal levels, reaching saturation. Multiple regression analysis showed that the most significant factors influencing serum sulfatide levels were MDA and total cholesterol content.. The current results show that over the long term, the internal improvement brought about by successful KT can normalize OS. Oxidative normalization was significantly correlated with the restoration of serum sulfatide levels, which were also influenced by lipoprotein metabolism. The amelioration of serum sulfatide levels might contribute to the low incidence of CVD in KT recipients.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Cholesterol; Female; Humans; Incidence; Japan; Kidney; Kidney Transplantation; Longitudinal Studies; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Regression Analysis; Renal Insufficiency, Chronic; Risk Factors; Sulfoglycosphingolipids

We recently proposed serum sulfatides as a novel biomarker for cardiovascular disease in patients with end-stage renal failure (ESRF), based on the possible antithrombotic properties of this molecule. In this earlier study, the level of serum sulfatides was gradually decreased in parallel with kidney dysfunction; however the precise mechanism underlying this decrease was unknown. The aim of the present study was to investigate the mechanism underlying the decrease in serum sulfatide levels caused by kidney dysfunction in an experimental animal model. To produce a kidney dysfunction animal model, we prepared a mouse model of protein overload nephropathy. Using high-throughput analysis combined with matrix-assisted laser desorption ionisation time-of-flight mass spectrometry, we measured the levels of sulfatides in the sera, livers, small intestines and kidneys of protein overload nephropathy mice. As the disease progressed, the levels of sulfatides in sera decreased. Also, the levels in livers and small intestines decreased in a similar manner to those in sera, to approximately 60% of the original levels. On the contrary, those in kidneys increased by approximately 1.4-fold. Our results indicate that kidney dysfunction affects the levels of sulfatides in lipoprotein-producing organs, such as livers and small intestines, and lowers the levels of sulfatides in sera.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Intestine, Small; Kidney Diseases; Liver; Male; Mice; Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfoglycosphingolipids

Sulfatides, normal components of serum lipoproteins, may play an important role in cardiovascular disease due to their various modulatory functions in haemostasis. The incidence of cardiovascular disease in patients with end-stage renal failure undergoing maintenance hemodialysis has been reported to be approximately 10 to 30 times higher than that in the general population. To elucidate the possible roles of serum sulfatides in this high incidence, we measured the level of sulfatides in 59 such patients, by converting them to lysosulfatides according to a recently developed quantitative, qualitative, high-throughput technique using matrix-assisted laser desorption ionization-time of flight mass spectrometry. The mean level of sulfatides in patients 3.58 +/- 1.18 nmol/ml was significantly lower than that in age-matched normal subjects (8.21 +/- 1.50 nmol/ml; P < 0.001). Patients receiving maintenance hemodialysis over a longer period had lower levels of sulfatides. When the mean levels of sulfatides were compared between patients with cardiovascular disease (N = 22) and those without the disease (N = 37), the level in the former group 2.85 +/- 0.67 nmol/ml was found to be significantly lower than that in the latter group 4.01 +/- 1.22 nmol/ml (P < 0.001). These findings reveal a close correlation between low levels of serum sulfatides and a high risk of cardiovascular disease in these patients. Determination of the level of serum sulfatides can contribute to predictions of the incidence of cardiovascular disease in patients with end-stage renal failure undergoing maintenance hemodialysis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Female; Humans; Kidney Failure, Chronic; Male; Mass Spectrometry; Middle Aged; Renal Dialysis; Sulfoglycosphingolipids