Insulin can regulate the expression of eNOS gene, mediated by the activation of PI-3 kinase, in endothelial cells and microvessels. Thus, insulin may chronically modulate vascular tone. The activation of PKC in the vascular tissues as in insulin resistance and diabetes may inhibit PI-3 kinase activity and eNOS expression and may lead to endothelial dysfunctions in these pathological states.

Induction of protein kinase C (PKC) pathway in the vascular tissues by hyperglycemia has been associated with many of the cellular changes observed in the complications of diabetes. Recently, we have reported that the use of a novel, orally effective specific inhibitor of PKC ␤ isoform (LY333531) normalized many of the early retinal and renal hemodynamics in rat models of diabetes. In the present study, we have characterized a spectrum of biochemical and molecular abnormalities associated with chronic changes induced by glucose or diabetes in the cultured mesangial cells and renal glomeruli that can be prevented by LY333531. Hyperglycemia increased diacylglycerol (DAG) level in cultured mesangial cells exposed to high concentrations of glucose and activated PKC ␣ and ␤ 1 isoforms in the renal glomeruli of diabetic rats. The addition of PKC ␤ selective inhibitor (LY333531) to cultured mesangial cells inhibited activated PKC activities by high glucose without lowering DAG levels and LY333531 given orally in diabetic rats specifically inhibited the activation of PKC ␤ 1 isoform without decreasing PKC ␣ isoform activation. Glucose-induced increases in arachidonic acid release, prostaglandin E 2 production, and inhibition of Na ϩ -K ϩ ATPase activities in the cultured mesangial cells were completely prevented by the addition of LY333531. Oral feeding of LY333531 prevented the increased mRNA expression of TGF-␤ 1 and extracellular matrix components such as fibronectin and ␣ 1(IV) collagen in the glomeruli of diabetic rats in parallel with inhibition of glomerular PKC activity. These results suggest that the activation of PKC, predominately the ␤ isoform by hyperglycemia in the mesangial cells and glomeruli can partly contribute to early renal dysfunctions by alteration of prostaglandin production and Na

The results of the Diabetes Control and Complications Trial (1) have shown that strict glycemic control can prevent the onset and progression of diabetic complications. Several hypotheses such as hyperosmolarity, glycation end products, oxidant formation, abnormality of sorbitol and myoinositol metabolism, and diacylglycerol (DAG)-protein kinase C (PKC) activation (2-6) have been proposed to explain the various pathologic changes induced by hyperglycemia. It is likely that glucose and its metabolites mediate their adverse effects by altering the various signal transduction pathways, which are used by vascular cells to perform their functions and to maintain cellular integrity. We and others (6-16) have recently identified that the activation of PKC, especially the β isoforms, could be responsible for some of the vascular dysfunctions observed in the diabetic state. Some of these changes in the vascular cells are increases in contractility, cellular proliferation, permeability, and extracellular matrix and cytokine production (5, 6). However, it has not been determined whether hyperglycemia and its metabolites can affect other signal transduction systems and/or the cellular targets of DAG-PKC activation.Recently, several mitogen-activated protein (MAP) kinase signal transduction pathways have been characterized . Extensive studies have clarified that they are activated by multistep phosphorylation cascades after ligand-cell surface receptor binding and and that they transmit signals to cytosolic and nuclear targets (17). The classic MAP kinases, extracellular signal-regulated protein kinase (ERK)-1 and -2, are activated through Ras-dependent signal transduction pathway by hormones and growth factors, leading to cellular proliferation and differentiation by stimulating transcription factors that induce the expression of c-fos and other growth-responsive genes (18,19). With respect to ERKs, Haneda et al. (20) recently showed that high glucose levels phosphorylated ERKs through PKC activation in rat glomeruli and mesangial cells.In contrast, two additional parallel signal transduction pathways, c-jun NH 2 -terminal protein kinase (JNK) and p38 MAP kinases, have also been identified (21-38). These pathways are strongly activated by environmental stress factors including ultraviolet light (22, 23), oxidants (25, 26), lipopolysaccharide (27-29), osmotic stress (30-33), heat shock (34), and proinflammatory cytokines such as tumor necrosis factor-α (ΤΝF-α) and interleukin-1 (35-38), leading to alterations in cell growth, prostanoid productions, and other cellular dysfunctions (39, 40).Because many similar stress factors as already mentioned here have been identified to be present in diabetes, it is reasonable to suspect that p38 MAP kinase activation could also be involved in mediating hyperglycemia's adverse effects. In this study, we have characterized the mechanisms by which elevation of glucose levels activated p38 MAP kinase in cultured vascular cells and aorta derived from diabetic rats. Hyperglycemia can cause va...

Aim: Small, dense low density lipoprotein (sLDL) is known as an atherogenic lipoprotein and is often associated with metabolic syndrome (MS). A high frequency of sLDL is found in hypertriglyceridemic subjects. Also, fatty liver (FL) is often associated with MS; therefore, we studied whether the association of FL increases sLDL-cholesterol (C ) in subjects with MS. Methods: In total, 207 patients were enrolled in this study and FL was estimated by echogram. The presence of MS was diagnosed according to the Japanese Guidelines for the Definition of Metabolic Syndrome. Results: sLDL-C and sLDL-C/LDL-C in the MS group were higher than in the non-MS group. Also, sLDL-C and sLDL-C/LDL-C in the FL group were higher than in the non-FL group. The simple correlation coefficient (r) between plasma triglyceride and sLDL-C or sLDL-C/LDL-C in all subjects was 0.36 and 0.51. In the MS group, r values were 0.32 and 0.52 while, in the non-FL group, r was 0.32 and 0.38, respectively. Two-way ANOVA revealed that FL was a powerful determinant of plasma sLDL-C and sLDL-C/LDL-C, but MS was not. When we divided all subjects into four groups, i.e., MS( )FL( ), MS( )FL( ), MS( )FL( ) and MS( )FL( ), sLDL-C/LDL-C of MS( )FL(