Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension and accelerated atherosclerosis. In the present study, the mechanisms of vasomotor dysfunction, Akt (Thr 308 and Ser 473 ) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr 308 ) level in arteries from diabetic patients was reduced to about one-half of the level in nondiabetic patients, suggesting impaired insulin signaling in human diabetic vascular tissue. Augmented vasoconstriction was observed in diabetic arteries, due in part to deficiency of basal and stimulated NO production. This correlated with decreased endothelial NO synthase expression and activity in diabetic vessels. The sensitivity of diabetic vessels to the NO donor, sodium nitroprusside, was reduced as well, suggesting that NO breakdown and/or decreased sensitivity of smooth muscle to NO are also responsible for abnormal vasoconstriction. In addition, the abnormal vasoconstriction in diabetic vessels was not completely abolished in the presence of N-nitro-L-arginine methyl ester, revealing that NO-independent mechanisms also contribute to vasomotor dysfunction in diabetes. In conclusion, diabetes downregulates the Akt-signaling pathway and compromises human arterial function through a decrease in NO availability as well as through NO-independent mechanisms. Diabetes 54:2415-2423, 2005

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Thiazolidinediones, such as pioglitazone, seem to exert direct antiatherosclerotic and antirestenotic effects on type 2 diabetes, in part due to an induction of vascular smooth muscle cell (VSMC) apoptosis. We aimed to study the role of transforming growth factor (TGF)-␤ in rat aortic VSMC. Pioglitazone at 100 mol/l increased apoptosis without affecting DNA synthesis, and this effect was reversed by an anti-TGF-␤1 antibody. Extracellular TGF-␤1 levels were rapidly increased after treatment with pioglitazone in a peroxisome proliferator-activated receptor (PPAR)-␥-dependent mechanism because this secretion was blocked by the PPAR-␥ inhibitor GW9662. Pioglitazone subsequently increased the nuclear recruitment of phospho-Smad2, without any effect on protein expression. According to our results, we propose that the apoptotic effect of pioglitazone on VSMC depends on the following sequence: PPAR-␥ activation, TGF-␤1 release, and selective phospho-Smad2 nuclear recruitment. Management of Smad signaling on VSMC might provide future clinical benefits in vascular diseases. Diabetes 54: [811][812][813][814][815][816][817] 2005 T ype 2 diabetes is a major risk factor for atherosclerosis, the leading cause of morbidity and mortality in developed countries (1). In addition, diabetic patients show an increased risk for suffering postangioplasty restenosis (2). Vascular wall size depends on a relative balance between proliferation and apoptosis (3). When the ratio of proliferation to apoptosis increases, an early atherosclerotic plaque or a postangioplasty restenosis is faced.Thiazolidinediones (TZDs) are an emerging class of antidiabetic drugs that enhance insulin sensitivity in a peroxisome proliferator-activated receptor (PPAR)-␥-dependent fashion (4). However, they have also been demonstrated to exert some direct effects in decreasing neointimal growth after balloon injury (5) and angioplasty (6), two situations with an increased ratio for vascular smooth muscle cell (VSMC) proliferation to apoptosis. Many of the studies concerning the cellular effects of TZD have focused on cell cycle and DNA synthesis regulation. Surprisingly, these effects seem to be PPAR-␥ independent (7). On the other hand, at higher doses, TZDs have been proven to induce apoptosis in VSMCs by involving PPAR-␥ (8).Transforming growth factor (TGF)-␤1 is an essential cytokine involved in the control of the balance between proliferation and apoptosis in VSMCs. TZDs and TGF-␤1 share the induction of apoptosis by similar mechanisms, such as GADD45 (9,10). In addition, some crosstalk between TGF-␤1 and PPAR-␥ has been described; thus, in the long term, TGF-␤1 inhibits PPAR-␥ expression (11), whereas PPAR-␥ agonists and PPAR-␥ itself interact with the TGF-␤1 signaling pathway by inhibiting Smad3 (12). Therefore, Smad2 appears as a likely target for TGF-␤ in TZD-treated VSMCs.In the present study, we show that the apoptotic effect of the TZD pioglitazone in VSMC depends on the following sequence: PPAR-␥ agonism, rapid TGF-␤1 autocrine secretion, and select...

An emerging body of evidence suggests that vascular remodeling in diabetic patients involves a perturbation of the balance between cell proliferation and cell death. Our aim was to study whether arteries and vascular smooth muscle cells (VSMCs) isolated from diabetic patients exhibit resistance to apoptosis induced by several stimuli. Internal mammary arteries (IMAs) were obtained from patients who had undergone coronary artery bypass graft surgery. Arteries from diabetic patients showed increasing levels of Bcl-2 expression in the media layer, measured by immunofluorescence and by Western blotting. Human IMA VSMCs from diabetic patients showed resistance to apoptosis, measured as DNA fragmentation and caspase-3 activation, induced by C-reactive protein (CRP) and other stimuli, such as hydrogen peroxide and 7␤-hydroxycholesterol. The diabetic cells also exhibited overexpression of Bcl-2. Knockdown of Bcl-2 expression with Bcl-2 siRNA in cells from diabetic patients reversed the resistance to induced apoptosis. Consistent with the above, we found that pretreatment of nondiabetic VSMCs with high glucose abolished the degradation of Bcl-2 induced by CRP. Moreover, cell proliferation was increased in diabetic compared with nondiabetic cells. This differential effect was potentiated by glucose. We conclude that the data provide strong evidence that arterial remodeling in diabetic patients results from a combination of decreased apoptosis and increased proliferation. Diabetes 55: [1243][1244][1245][1246][1247][1248][1249][1250][1251] 2006

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We showed that long-term treatment with DOBE attenuated the progression of diabetic retinopathy and the alterations in vascular reactivity in streptozotocin-induced diabetic rats.

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