Genetic deletion of p66 ^Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress

Abstract

Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66 Shc adaptor protein controls cellular responses to oxidative stress. Mice lacking p66 Shc (p66 Shc؊/؊ ) have increased resistance to ROS and prolonged life span. The present work was designed to investigate hyperglycemia-associated changes in endothelial function in a model of insulin-dependent diabetes mellitus p66 Shc؊/؊ mouse. p66 Shc؊/؊ and wild-type (WT) mice were injected with citrate buffer (control) or made diabetic by an i.p. injection of 200 mg of streptozotocin per kg of body weight. Streptozotocin-treated p66 Shc؊/؊ and WT mice showed a similar increase in blood glucose. However, significant differences arose with respect to endothelial dysfunction and oxidative stress. WT diabetic mice displayed marked impairment of endotheliumdependent relaxations, increased peroxynitrite (ONOO ؊ ) generation, nitrotyrosine expression, and lipid peroxidation as measured in the aortic tissue. In contrast, p66 Shc؊/؊ diabetic mice did not develop these high-glucose-mediated abnormalities. Furthermore, protein expression of the antioxidant enzyme heme oxygenase 1 and endothelial NO synthase were up-regulated in p66 Shc؊/؊ but not in WT mice. We report that p66 Shc؊/؊ mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66 Shc adaptor protein is part of a signal transduction pathway relevant to hyperglycemia vascular damage and, hence, may represent a novel therapeutic target against diabetic vascular complications.

Alteration of p66shc is associated with endothelial dysfunction in the abdominal aortic coarctation of rats

“…The pivotal role of p66shc in increasing the intracellular ROS levels is well established [7,9,10]. Especially, the genetic deletion of p66shc prevents the hyperglycemia-induced or age-related endothelial dysfunction and oxidative stress [11,29]. An important question in this study is how the changes in blood pressure affect the impaired endothelium-dependent relaxation of the vascular wall.…”

“…Recently, genetic deletion of p66shc has been found to prevent the hyperglycemia-induced endothelial dysfunction and oxidative stress [11]. RNAi-mediated down-regulation of endogenous p66shc has led to the activation of phosphorylation of endothelial nitric oxide synthase (eNOS) at S1177 [12,13].…”

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

“…but not in glomerular endothelial cells, constitutes an additional mechanism predisposing podocytes to ROS-induced injury. Hitherto, studies exploring vascular disease have focused on the effect of aPC or p66 Shc in endothelial cells (26), but the effect of aPC on p66 Shc in podocytes reported here implies that perivascular cells should be equally considered and evaluated. Along this line, a potential role for aPC outside the vascular compartment (in microglia and astrocytes) has been reported in a murine model of amyotrophic lateral sclerosis (4).…”

Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis

“…The potent stress response regulator Foxo3A is a downstream target of p66ShcA redox signals that phosphorylate key regulatory sites, inhibiting transcription of Foxo3A stress-related gene products (11,12). Because phosphorylation at a critical Ser-36 residue activates p66ShcA redox activity (13), mutation at this site should inhibit transmission of reactive oxygen species (ROS)-dependent signals that target Foxo3A and genomic DNA, triggering activation of the apoptosis program. We have proposed a model in which inhibition of p66ShcA redox activity results in the activation of a Foxo3A-dependent stress program that shifts the phenotype of podocytes expressing HIV-1 genes away from apoptosis and toward cell survival.…”