Protein Kinase C–Dependent Increase in Reactive Oxygen Species (ROS) Production in Vascular Tissues of Diabetes

Abstract

Abstract. Hyperglycemia seems to be an important causative factor in the development of micro-and macrovascular complications in patients with diabetes. Several hypotheses have been proposed to explain the adverse effects of hyperglycemia on vascular cells. Both protein kinase C (PKC) activation and oxidative stress theories have increasingly received attention in recent years. This article shows a PKC-dependent increase in oxidative stress in diabetic vascular tissues. High glucose level stimulated reactive oxygen species (ROS) production via a PKC-dependent activation of NAD(P)H oxidase in cultured aortic endothelial cells, smooth muscle cells, and renal mesangial cells. In addition, expression of NAD(P)H oxidase components were shown to be upregulated in vascular tissues and kidney from animal models of diabetes. Furthermore, several agents that were expected to block the mechanism of a PKCdependent activation of NAD(P)H oxidase clearly inhibited the increased oxidative stress in diabetic animals, as assessed by in vivo electron spin resonance method. Taken together, these findings strongly suggest that the PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased oxidative stress in diabetes.Hyperglycemia seems to be an important causative factor in the development of micro-and macrovascular complications in patients with diabetes (1,2). Various pathophysiological and biochemical mechanisms have been proposed to explain the adverse effects of hyperglycemia on vascular cells (3-6). Among various possible mechanisms, it is widely accepted that high glucose level and a diabetic state induce the persistent activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway in micro-and macrovascular tissues of diabetic animals and of patients with diabetes (7-12). Because PKC is a critical intracellular signaling molecule that can regulate many vascular functions, it is to be expected that activation of PKC may cause alteration in various vascular functions in diabetes. However, accumulating evidence has shown that oxidative stress also may play a role in the development of diabetic vascular complications. A number of in vitro and in vivo studies suggest that the production of reactive oxygen species (ROS) is increased in diabetes (13-16). It has been postulated that ROS production in diabetes may be enhanced by hyperglycemia through various mechanisms such as enhanced formation of glycation products (17), altered polyol pathway activity (18), and increased superoxide release from mitochondria (19). In contrast, attention is increasingly focused on NAD(P)H oxidase as the most important source of ROS production in blood vessels (20 -23). Recent reports have implicated that this oxidase may be involved in the pathophysiology of various vascular diseases, including hypercholesterolemia (24), atherosclerosis (25-27), and hypertension (28). In this review, we show that a PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased ROS ...

Phenotype-specific inhibition of the vascular smooth muscle cell cycle by high glucose treatment

“…Therefore, our data showing that glucose treatment increased the production of ROS in epithelioid SMCs further support the involvement of the hexosamine pathway. These results are also consistent with data in the literature showing that an increase in ROS production concurs with PKC activation in response to glucose treatment [44].…”

Myogenic tone and reactivity of cerebral arteries in Type II diabetic BBZDR/Wor rat

“…This is in accordance with the earlier supposition that in diabetic arterial wall, PKC activation is higher via PLC-mediated production of diacylglycerol (DAG) that activates PKC (Inoguchi et al, 2003). In the present study, the inhibitory potency (pIC 50 ) of PLC inhibitor, U-73122, was taken as a measure of PLC-activation involved in the myogenic tone.…”

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

“…The NADPH oxidase complex consists of the membrane-associated flavocytochrome b 558 protein, which is composed of gp91 phox and p22 phox , and the cytosolic components p47 phox , p67 phox and p40 phox [35]. It has been reported that the diacylglycerol-protein kinase C pathway is stimulated in the malformed embryos of diabetic mice [36] and that protein kinase C stimulates NADPH oxidase expression [37]. Thus, the data we present here suggest that an increase in NADPH oxidase expression and subsequent ROS production result in the elevation of iNOS expression in embryos of diabetic mice.…”