Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity

Abstract

Diabetes mellitus is one of the major risk factors for atherosclerosis and is associated with an increased incidence of coronary heart diseases and cerebrovascular diseases [1,2]. The high prevalence of these macrovascular diseases in diabetic patients can be explained by hyperglycaemia in itself [3] as well as by the increased frequency of conventional risk factors such as hypertension, hyperlipidemia, obesity, and smoking.The proliferation of vascular smooth muscle cells is one of the characteristic features of atherosclerosis [4]. According to previous reports [4,5], platelet-derived growth factor (PDGF) plays an important part in the accelerated proliferation of smooth muscle Diabetologia (2001) Abstract Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-b specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-bII isoform and PDGF-b receptor protein, free cytosolic NAD + :NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKCbII isoform and PDGF-b receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-b receptor were more prominent than those of LY333 531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD + :NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-bII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-b receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication. [Diabetologia (2001) 44: 480±487]

Contribution of Aldose Reductase to Diabetic Hyperproliferation of Vascular Smooth Muscle Cells

“…Additionally, inhibition of aldose reductase, by promoting HNE accumulation, could inhibit mitogenic signaling pathways activated by glucose. It has been shown that inhibition of aldose reductase prevents hyperglycemia-induced (14,15,44) and growth factor-induced (17) PKC activation, which is essential for SMC growth in high glucose (45). Regardless of the mechanism, because aldose reductase inhibitors prevent intimal expansion (this study) as well as inflammation associated with nuclear factor-B activation (16,17,46), without drastically decreasing lesion cellularity (Fig.…”

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

“…Taking into consideration that diabetic kidney accumulates AGE [13], it is quite plausible that increased AR activity contributes to renal oxidative stress by promoting nonenzymatic glycation. Several groups have reported that increased AR activity leads to PKC activation in glomerular mesangial cells [78] and vasculature [79,80]. The latter probably occurs due to AR-dependent decrease in free cytosolic NAD + /NADH ratio and associated diversion of the glycolytic flux toward the increased formation of α-glycerophosphate and diacylglycerol, a PKC activator.…”

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

“…However, the effects of IGF-1 and the expression of TGF-β have been shown to be influenced by PKC activity [36,37]. Interestingly, hyperglycaemia-induced increase in PKC activity can be reduced by aldose reductase inhibitors [38,39], although other studies have reported ineffectiveness of such treatment [40].…”