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Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50-75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P < 0.05) and impaired vasodilation (P < 0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P< 0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P < 0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1beta (interleukin-1beta) expression in intact epidermis, TNF-alpha (tumour necrosis factor-alpha) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-beta (transforming growth factor-beta) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.

Abstract-Activation of nuclear hormone receptor peroxisome proliferator-activated receptor ␤/␦ (PPAR␤) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPAR␤ agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22 phox and p47 phox proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1␤, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPAR␤ activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPAR␤ activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPAR␤ as a new therapeutic target in hypertension. T he peroxisome proliferator-activated receptors (PPARs) PPAR␣, PPAR␤/␦, and PPAR␥ are members of the nuclear hormone receptor superfamily. PPARs were initially believed to regulate genes involved only in lipid and glucose metabolism. 1 However, in recent years, evidence suggests that activation of PPAR␣ or PPAR␥ may exert cardiovascular protection beyond their metabolic effects. 2 In fact, PPAR␣ or PPAR␥ agonists exert antihypertensive effects in both human and animal models with or without metabolic disorders. [3][4][5][6] The mechanisms underlying the beneficial effects of PPARs beyond glucose and lipid metabolism may relate to their anti-inflammatory and antioxidant actions. 5 Thus, activation of both PPAR␣ or PPAR␥ antagonizes angiotensin II (Ang II) actions, including the activation of NADPH oxidase and the generation of reactive oxygen species, as well as the increase in proinflammatory mediators and adhesion molecules in blood vessels. 5,6 Activation of PPAR␤/␦ (PPAR␤) also exhibits antiinflammatory properties in the vessel wall by inhibiting the expression of vascular cell adhesion molecule 1 and monocyte chemoattractant prote...

The present study analysed the effects of the flavanol (2)-epicatechin in rats after chronic inhibition of NO synthesis with N G -nitro-L-arginine methyl ester (L-NAME), at doses equivalent to those achieved in the studies involving human subjects. Wistar rats were randomly divided into four groups: (1) control-vehicle, (2) L-NAME, (3) L-NAME-epicatechin 2 (L-NAME-Epi 2) and (4) L-NAME-epicatechin 10 (L-NAME-Epi 10). Rats were daily given by oral administration for 4 weeks: vehicle, (2)-epicatechin 2 or 10 mg/kg. Animals in the L-NAME groups daily received L-NAME 75 mg/100 ml in drinking-water. The evolution in systolic blood pressure and heart rate, and morphological and plasma variables, proteinuria, vascular superoxide, reactivity and protein expression at the end of the experiment were analysed. Chronic (2 )-epicatechin treatment did not modify the development of hypertension and only weakly affected the endothelial dysfunction induced by L-NAME but prevented the cardiac hypertrophy, the renal parenchyma and vascular lesions and proteinuria, and blunted the prostanoid-mediated enhanced endothelium-dependent vasoconstrictor responses and the cyclo-oxygenase-2 and endothelial NO synthase (eNOS) up-regulation. Furthermore, (2)-epicatechin also increased Akt and eNOS phosphorylation and prevented the L-NAME-induced increase in systemic (plasma malonyldialdehyde and urinary 8-iso-PGF 2a ) and vascular (dihydroethidium staining, NADPH oxidase activity and p22 phox up-regulation) oxidative stress, proinflammatory status (intercellular adhesion molecule-1, IL-1b and TNFa up-regulation) and extracellular-signal-regulated kinase 1/2 phosphorylation. The present study shows for the first time that chronic oral administration of (2)-epicatechin does not improve hypertension but reduced pro-atherogenic pathways such as oxidative stress and proinflammatory status of the vascular wall induced by blockade of NO production.Key words: (2 )-Epicatechin: N G -nitro-L-arginine methyl ester: Hypertension: Superoxide: Inflammation Flavanols, such as (2)-epicatechin, catechin and their oligomers, represent a major class of flavonoids that are commonly present in most higher plants, and with high content in certain foods, such as grapes, tea and cocoa. Several epidemiological investigations and dietary interventions in human subjects using flavanol-containing foods indicate an inverse relationship between flavanol intake and the risk of CVD (1 -5) . A very wide range of biological actions of a flavanol-rich diet support these potential cardiovascular protective effects including the improvement of vasodilation (6 -8) , blood pressure (9,10) , insulin resistance (11) , the attenuation of platelet reactivity (12) , and the improvement of immune responses and antioxidant defence system (13) . However, little is known about the molecular mechanisms of flavanol-mediated bioactivities in both humans and animals. The reasons for these shortcomings are, at least in part, based on the fact that food matrices contain a multitude of ...

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