Objective-There is still debate as to whether antiatherosclerotic effect of PPAR␥ ligands is dependant on PPAR␥ gene itself or some other pathway. Methods and Results-To investigate the effect of PPAR␥ gene modulation on neointima formation after balloon injury, we delivered adenoviral vectors expressing the wild-type (WT) dominant negative (DN) PPAR␥, or a control gene (␤-galactosidase [BG]) into carotid artery after balloon injury in rosiglitazone (a PPAR␥ ligand)-treated (Rϩ) (3 mg/kg/d) and nontreated (RϪ) rats. Two weeks after gene delivery, in both Rϩ and RϪ animals, the PPAR␥-WT gene transfer showed a significantly lower intima-media ratio (IMR) than control group. Moreover, the delivery of a PPAR␥-DN form showed the highest IMR (in RϩWT, 0.51Ϯ0.15; RϩBG, 0.89Ϯ0.14; RϩDN, 1.20Ϯ0.18, PϽ0.05 and in RϪWT, 0.91Ϯ0.21; RϪBG, 1.44Ϯ0.23; RϪDN, 1.74Ϯ0.29, PϽ0.05). Proliferation and migration showed same result pattern as IMR. In addition, apoptotic indices were significantly higher in the PPAR␥-WT gene transferred group than in the PPAR␥-DN group. Conclusions-In vivo transfer of the PPAR␥-WT gene was found to inhibit smooth muscle proliferation, sustain apoptosis, and reduce neointima formation after balloon injury irrespective of rosiglitazone treatment. These results indicate that PPAR␥ overexpression itself has a protective role against restenosis after balloon injury. Key Words: PPAR␥ Ⅲ vascular smooth muscle Ⅲ neointima Ⅲ proliferation Ⅲ apoptosis P eroxisome proliferator activated receptor gamma (PPAR␥) is a crucial factor in many cellular signaling pathways and is known to regulate several transcription factors. Researches have provided many insights into the pleiotropic role that PPAR␥ plays in cell proliferation, migration, and differentiation and adipocyte differentiation. In fact, PPAR␥ activation inhibits vascular smooth muscle cell (VSMC) proliferation, 1,2 for which several mechanisms have been suggested; blocking the reentry of quiescent VSMCs into the cell cycle, 3 inhibiting VSMC migration by controlling the mitogen-activated protein kinase (MAPK) pathway and the production of matrix metalloproteinase (MMP), 4,5 and reducing inflammation by attenuating cytokine production and nuclear factor-B transcription activity. 6,7 In the field of endocrinology and metabolism, PPAR␥ has been identified as an insulin sensitizer and as an important regulator of glucose metabolism. In fact, the diabetic milieu is associated with endothelial dysfunction and several therapeutic interventions have been tested in this context. 8 Moreover, PPAR␥ is a good target for the treatment of restenosis because its expression is found in all cells composing blood vessels (ie, monocytes, macrophages, and endothelial and VSMCs).It has recently been reported that the in vitro rosiglitazone treatment (a PPAR␥ ligand) results in a significant reduction in restenosis after coronary stent insertion. 9 Because PPAR␥ is located at a nodal point where multiple cell signals merge to control the proliferation and migration of VSMCs, it ma...

Epidermal growth factor (EGF) is synthesized in the pancreas and diabetic animals have low levels of EGF. However, the role of EGF in regulating the major function of the pancreas, insulin secretion, has not been studied. Here, we show that EGF rapidly increased insulin secretion in mouse pancreatic islets, as well as in a pancreatic β-cell line. These events were dependent on a Ca2+ influx and phospholipase D (PLD) activity, particularly PLD2, as determined using pharmacological blockers and molecular manipulations such as over-expression and siRNA of PLD isozymes. In addition, EGF also increased plasma insulin levels and mediated glucose lowering in normal and diabetic mice. Here, for the first time, we provide evidence that EGF is a novel secretagogue that regulates plasma glucose levels and a candidate for the development of therapeutics for diabetes.

Intrahepatic or intramuscular lipid (IHL/IML) content has been reported to be correlated with insulin resistance. Visceral fat has also been shown to be associated with insulin resistance. Thus, we investigated whether IHL/IML or visceral fat content is more closely associated with insulin resistance. Twenty Sprague‐Dawley rats were divided into two groups based on regular chow diet (RCD) or high‐fat diet (HFD; 40% fat). The insulin‐sensitivity index (ISI) was determined by euglycemic glucose clamp study, the amount of visceral fat by computed tomography (CT), and the IHL/IML content by magnetic resonance spectroscopy (MRS). Weight, food, and water intake, physical activity, energy expenditure, lipid profile, adiponectin, and high‐sensitivity C‐reactive protein (hsCRP) levels were measured. At the study end point, visceral fat, and the IHL/IML content were higher in the HFD group than in the RCD group. The IHL/IML content was more highly correlated with ISI than was visceral fat amount. Stronger correlations were also found between adiponectin or hsCRP level and IML/IHL content than visceral fat, especially in the HFD group. Furthermore, the IHL/IML content was significantly associated with the ISI in the multiple regression models but visceral fat was not. There was clear discrimination between RCD and HFD groups in scatter plots of IML/IHL against the ISI, but substantial overlap in that of visceral fat against the ISI. This result suggests that IHL/IML contents are closely related with insulin resistance or atherosclerosis and is a better metabolic index of insulin sensitivity than the visceral fat.

DL-3-n-butylphthalide (NBP) is a therapeutic drug used for ischemic stroke treatment. Here, we investigated the impact of NBP on the development of rat diabetic cataract induced by intraperitoneal injection of streptozotocin (STZ). NBP was then administrated by oral gavage for nine weeks. Cataract development was monitored through ophthalmoscope inspections. The levels of blood glucose and serum reactive oxygen species (ROS), malondialdehyde (MDA) and 8-Hydroxydeovexyguanosine (8-OHdG) were measured. Total and soluble protein and oxidative stress parameters, such as 2, 4- dinitrophenylhydrazone (DNP), 4-hydroxynonenal (4-HNE) and MDA in the lenses were determined by Western blot and thiobarbituric acid analyses. The expressions of NF-E2-related factor 2 (Nrf2) and its downstream antioxidant enzymes, thioredoxin (TRX), Catalase and nuclear accumulation of Nrf2 were determined by Western blot and immunohistochemistry analyses. We showed that NBP treatment significantly improved the cataract scores, the levels of DNP, 4-HNE, and MDA in the lens compared to the non-treated groups. NBP also enhanced the expressions of Nrf2, TRX and catalase in the lens of diabetic rats. In addition, NBP treatment also decreased levels of blood glucose, serum MDA and 8-OHdG. These results suggested that NBP treatment significantly delayed the onset and progression of diabetic cataract by inhibiting the oxidative stresses.