Abstract
A reduction of the nitric oxide (NO) action in vascular smooth muscle cells (VSMC) could play a role in the vascular damage induced by the glycaemic excursions occurring in diabetic patients; in this study, we aimed to clarify whether a short-term incubation of cultured VSMC with high glucose reduces the NO ability to increase cGMP and the cGMP ability to phosphorylate VASP at Ser-239. We observed that a 180 min incubation of rat VSMC with 25 mmol/L glucose does not impair the NO-induced cGMP increase but reduces VASP phosphorylation in response to both NO and cGMP with a mechanism blunted by antioxidants. We further demonstrated that high glucose increases radical oxygen species (ROS) production and that this phenomenon is prevented by the PKC inhibitor chelerythrine and the NADPH oxidase inhibitor apocynin. The following sequence of events is supported by these results: (i) in VSMC high glucose activates PKC; (ii) PKC activates NADPH oxidase; (iii) NADPH oxidase induces oxidative stress; (iv) ROS impair the signalling of cGMP, which is involved in the antiatherogenic actions of NO. Thus, high glucose, via oxidative stress, can reduce the cardiovascular protection conferred by the NO/cGMP pathway via phosphorylation of the cytoskeleton protein VASP in VSMC.
Highlights
Among the factors involved in the huge increase of cardiovascular risk occurring in diabetes mellitus, a pivotal role is played by a reduced synthesis and action of nitric oxide (NO) [1], a substance exerting a major role in vascular biology by a wide array of antihypertensive and antiatherogenic properties [2,3,4]
Since hyperglycaemia is the main biochemical feature of diabetes mellitus, we aimed to clarify in this study whether high glucose impairs in vascular smooth muscle cells (VSMC) the ability of NO to increase the synthesis of cGMP and to activate the downstream cascade of events leading to vasodilatory-stimulated phosphoprotein (VASP) phosphorylation; we aimed to clarify the mechanisms involved in this putative impairment, with a peculiar emphasis for the oxidative stress, which is deeply involved in the pathogenesis of diabetes vascular complications and mediates the vascular damage induced by hyperglycaemia [24, 25]
Our study shows that oxidative stress plays a pivotal role in the high glucose-induced impairment of the NO/cGMP signalling in VSMC, since this impairment is completely prevented by the antioxidant mixture superoxide dismutase (SOD) + catalase
Summary
Among the factors involved in the huge increase of cardiovascular risk occurring in diabetes mellitus, a pivotal role is played by a reduced synthesis and action of nitric oxide (NO) [1], a substance exerting a major role in vascular biology by a wide array of antihypertensive and antiatherogenic properties [2,3,4] As it is widely recognized, in diabetes mellitus there is a reduced synthesis of NO by vascular endothelium, mirrored by a reduction of the so-called “endothelial-dependent relaxation,” that is, the “in vivo” vasodilation induced by agents able to stimulate the endothelial synthesis of NO [5, 6]. The influence of cGMP on the cardiovascular system is exerted by activating cGMP-dependent protein kinases and phosphatases [15, 17]
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