heparitin-sulfate and Diabetic-Angiopathies

Insulin-dependent diabetic patients with increased urinary albumin excretion are characterized by elevated blood pressure and declining kidney function. In addition, such patients have a high risk of atherosclerotic vascular disease, proliferative retinopathy, and cardiomyopathy, suggesting that albuminuria is a marker of widespread vascular dysfunction. Increased transport of macromolecules across the vascular wall, elevated plasma levels of von Willebrand factor, and impaired fibrinolytic capacity have been demonstrated in albuminuric patients. The cause of this vascular vulnerability in susceptible patients is unknown, but increasing evidence has suggested that loss of the proteoglycan heparan sulfate in the vasculature may explain the widespread nature of the disease. Heparan sulfate is important for the glomerular endothelial cell and basement membrane charge densities, the anticoagulant properties of the vessel wall, and the growth regulation of intimal smooth muscle cells. Recent studies have shown that heparin increases the biosynthesis of heparan sulfate in endothelial cell cultures and prevents the characteristic glomerular basement membrane thickening when given to diabetic rats. Moreover, heparin has been shown to reduce albuminuria in patients with incipient diabetic nephropathy. Although increasing evidence supports the hypothesis that loss of heparan sulfate may play a pathophysiological role in the development of diabetic vascular complications, there are still many unresolved problems. What are the mechanisms of action of glycosaminoglycans at the molecular biology level, and how can we select compounds without anticoagulant activity suitable for long-term use in the prevention and treatment of late diabetic complications?

Topics: Albuminuria; Animals; Basement Membrane; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Proteoglycans

Glycocalyx dysfunction is believed as the first step in diabetic vascular disease. However, few studies have systematically investigated the influence of HG on the glycocalyx as a whole and its major constituent glycans towards one type of cell. Furthermore, most studies utilized traditional two-dimensional (2D) cultures in vitro, which can't provide the necessary fluid environment for glycocalyx. Here, we utilized vascular glycocalyx on chips to evaluate the changes of glycocalyx and its constituent glycans in HG induced HUVECs. Fluorescence microscopy showed up-regulation of hyaluronan (HA) but down-regulation of heparan sulfate (HS). By analyzing the metabolic enzymes of both glycans, a decrease in the ratio of synthetic/degradative enzymes for HA and an increase in that for HS were demonstrated. Two substrates (UDP-GlcNAc, UDP-GlcA) for the synthesis of both glycans were increased according to omics analysis. Since they were firstly pumped into Golgi apparatus to synthesize HS, less substrates may be left for HA synthesis. Furthermore, the differential changes of HA and HS were confirmed in vessel slides from db/db mice. This study would deepen our understanding of impact of HG on glycocalyx formation and diabetic vascular disease.

Topics: Animals; Diabetic Angiopathies; Glucose; Heparitin Sulfate; Hyaluronic Acid; Mice; Uridine Diphosphate

Pathogenesis, frequency, and management of heparin-induced thrombocytopaenia are well-known. They may be related with both unfractioned heparin and low-molecular weight heparin. Suspected heparin must be discontinued as soon as the diagnosis is established. Orgaran (danaparoid sodium) may be used for management of patients with heparin-associated thrombocytopaenia but can itself be associated with a thrombocytopaenia. Our case report allows us to catch in mind such a crossed complication.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Captopril; Carotid Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Hypertension; Stroke; Thrombocytopenia

The primary etiologic factor in diabetic glomerulosclerosis appears to be an overproduction of transforming growth factor-beta by mesangial cells, which in turn reflects a hyperglycemically mediated overactivation of protein kinase C (PKC) throughout the glomerulus. Membrane-active antioxidants, fish oil, and angiotensin-converting enzyme inhibitors can act to down-regulate glomerular PKC activity, via a variety of mechanisms that may include activation of diacylglycerol kinase and suppression of phosphatidate phosphohydrolase, support of endothelial nitric oxide and heparan sulfate production, inhibition of thromboxane and angiotensin synthesis/activity, and correction of glomerular hypertension. The beneficial impact of these measures on vascular endothelial function may be of more general utility in the prevention of diabetic complications such as retinopathy, neuropathy, and atherosclerosis. Adjunctive use of gamma-linolenic acid is indicated for prevention of neuropathy, and it is conceivable that bioactive chromium will have protective activity not solely attributable to improved glycemic control. Re-establishing euglycemia must clearly remain the core strategy for preventing diabetic complications, but when glycemic control remains suboptimal, practical, safe measures are at hand for decreasing risk.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Diabetic Angiopathies; Diabetic Nephropathies; Enzyme Activation; Fish Oils; Heparitin Sulfate; Humans; Hyperglycemia; Kidney Glomerulus; Lipid Peroxidation; Models, Biological; Nitric Oxide; Protein Kinase C; Thromboxane A2; Transforming Growth Factor beta