Objective-Proliferation of smooth muscle cells (SMC) in response to vascular injury is central to neointimal vascular remodeling. There is accumulating evidence that histone acetylation constitutes a major epigenetic modification for the transcriptional control of proliferative gene expression; however, the physiological role of histone acetylation for proliferative vascular disease remains elusive. Methods and Results-In the present study, we investigated the role of histone deacetylase (HDAC) inhibition in SMC proliferation and neointimal remodeling. We demonstrate that mitogens induce transcription of HDAC 1, 2, and 3 in SMC. Short interfering RNA-mediated knockdown of either HDAC 1, 2, or 3 and pharmacological inhibition of HDAC prevented mitogen-induced SMC proliferation. The mechanisms underlying this reduction of SMC proliferation by HDAC inhibition involve a growth arrest in the G 1 phase of the cell cycle that is due to an inhibition of retinoblastoma protein phosphorylation. HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21 Cip1 and p27 Kip. Furthermore, HDAC inhibition repressed mitogen-induced cyclin D1 mRNA expression and cyclin D1 promoter activity. As a result of this differential cell cycle-regulatory gene expression by HDAC inhibition, the retinoblastoma protein retains a transcriptional repression of its downstream target genes required for S phase entry. Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury. Conclusion-These

Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction.

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological studies linking ELS to the development of cardiovascular disease and to discuss the potential molecular mechanisms identified from animal studies. Overall, this review reveals the need for future investigations to further clarify the molecular mechanisms of ELS in order to develop more personalized therapeutics to mitigate the long-term consequences of chronic behavioral stress including cardiovascular and heart disease in adulthood.

nature publishing group short communications integrative PhysiologyChronic oxidative stress has been implicated in the development of type 2 diabetes and its associated cardiovascular complications (1,2). Reactive oxygen species (ROS) accumulate in obesity and considerable experimental and clinical data have linked oxidative stress to insulin resistance and β-cell dysfunction (1,3). At the cellular level, chronic oxidative stress resulting from prolonged exposure to high concentrations of ROS alters insulin-stimulated glucose update, an effect that is thought to be mediated by impaired insulin signaling (2,3). However, considering that certain ROS may also serve as important second messengers and signaling intermediates (4), the causal contribution of physiological concentrations of ROS to insulin resistance and obesity remains controversial. For example, transient and low dose concentrations of H 2 O 2 enhance insulin sensitivity (5,6), indicating that the role of ROS in glucose metabolism may depend on the ROS concentration and the mechanisms of their generation. Since glutathione peroxidase (GPx) constitutes the principal antioxidant defense system to scavenge physiological concentrations of H 2 O 2 in mammals (6), we investigated in this study the role of pharmacological glutathione depletion on diet-induced obesity and insulin sensitivity. Surprisingly, depletion of endogenous glutathione protected mice from obesity, preserved insulin sensitivity, and increased energy expenditure, pointing to a more complex role of endogenous ROS in diabetes and energy balance than previously anticipated. Methods and Proceduresanimal experiments C57BL/6 mice were obtained from The Jackson Laboratory. All mice were housed in plexiglas-ventilated cages within a pathogen-free barrier facility that maintained a 12-hour light/12-hour dark cycle. Mice had access to autoclaved water and pellet food ad libitum. Prior to 11 weeks of age, all mice were fed a standard rodent chow diet containing ~5% kcal fat (Harlan Teklad). At 11 weeks of age, all mice were fed a high-fat diet (HFD) containing 45% kcal from fat (Research Diets, New Brunswick, NJ). During this period L-buthionine-(S,R)-sulfoximine (BSO, Sigma-Aldrich, St Louis, MO) was administered in the drinking water of the treatment group at a concentration of 30 mmol/l. BSO was dissolved in diH 2 O and filtered before use. Weight gain was monitored weekly. Body compositionBody composition was analyzed after 6 weeks of HFD feeding using quantitative magnetic resonance imaging (EchoMRI, Echo Medical Systems, Houston, TX) as described (7). Metabolic measurementsGlucose tolerance tests were performed in HFD-fed animals after an overnight fasting period (n = 10 and n = 9 for HFD + BSO, respectively). Following an intraperitoneal injection of glucose dissolved in water (2 g/kg body weight), blood glucose levels were analyzed before and 15, 30, 60, 90, and 120 min after injection using a Freestyle Flash Glucometer (Abbott Laboratories, Chicago, IL). Insulin sensitivity was analyzed in f...

Exposure to Early Life Stress (ELS) is associated with behavioral-related alterations, increases in body mass index and higher systolic blood pressure in humans. Postnatal maternal separation and early weaning (MSEW) is a mouse model of neglect characterized by a long-term dysregulation of the neuroendocrine system. Objectives Given the contribution of adrenal-derived hormones to the development of obesity, we hypothesized that exposure to MSEW could contribute to worsen the cardiometabolic function in response to chronic high fat diet (HF) feeding by promoting adipose tissue expansion and insulin resistance. Subjects MSEW was performed in C57BL/6 mice from postnatal days 2–16 and weaned at postnatal day 17. Undisturbed litters weaned at postnatal day 21 served as the control (C) group. At the weaning day, mice were placed on a low fat diet (LF) or HF for 16 weeks. Results When fed a LF, male and female mice exposed to MSEW display similar body weight but increased fat mass compared to controls. However, when fed a HF, only female MSEW mice display increased body weight, fat mass and adipocyte hypertrophy compared with controls. Also, female MSEW mice display evidence of an early onset of cardiometabolic risk factors, including hyperinsulinemia, glucose intolerance and hypercholesterolemia. Yet, both male and female MSEW mice fed a HF show increased blood pressure compared with controls. Conclusions This study shows that MSEW promotes a sex-specific dysregulation of the adipose tissue expansion and glucose homeostasis that precedes the development of obesity-induced hypertension.