Troy J. Pereira

Resveratrol prevents hypertension and cardiac hypertrophy in hypertensive rats and mice

Resveratrol (RESV) is a polyphenol with pleiotropic effects that include reduction of oxidative stress and increased vascular nitric oxide (NO) production. However, whether or not RESV can prevent rises in blood pressure (BP) is controversial and remains to be firmly established. The purpose of this study was to determine whether RESV attenuates elevated BP and subsequent adaptive cardiac hypertrophy and to better understand the mechanisms involved. The spontaneously hypertensive rat (SHR) and the angiotensin (Ang)-II infused mouse were used as hypertensive models. Compared to a standard control diet, consumption of diets containing RESV by SHRs and Ang-II hypertensive mice, markedly prevented rises in systolic BP. In addition, flow-mediated vasodilation was significantly improved by RESV in SHRs. RESV also reduced serum and cardiac levels of the lipid peroxidation by-product, 4-hydroxy-2-nonenal in the hypertensive rodents and inhibited the production of superoxide in human-derived endothelial cells. Analysis of mesenteric arteries from SHRs and Ang-II infused mice demonstrated that RESV increased endothelial NO synthase (eNOS) phosphorylation by enhancing the LKB1/adenosine monophosphate (AMP)-activated protein kinase (AMPK) signal transduction pathway. Moreover, RESV reduced hypertrophic growth of the myocardium through reduced hemodynamic load and inhibition of the p70 S6 kinase pro-hypertrophic signaling cascade. Overall, we show that high dose RESV reduces oxidative stress, improves vascular function, attenuates high BP and prevents cardiac hypertrophy through the preservation of the LKB1-AMPK-eNOS signaling axis.

Influence of maternal overnutrition and gestational diabetes on the programming of metabolic health outcomes in the offspring: experimental evidence.

The incidence of obesity and type 2 diabetes mellitus have risen across the world during the past few decades and has also reached an alarming level among children. In addition, women are currently more likely than ever to enter pregnancy obese. As a result, the incidence of gestational diabetes mellitus is also on the rise. While diet and lifestyle contribute to these trends, population health data show that maternal obesity and diabetes during pregnancy during critical stages of development are major factors that contribute to the development of chronic disease in adolescent and adult offspring. Fetal programming of metabolic function, through physiological and (or) epigenetic mechanisms, may also have an intergenerational effect, and as a result may perpetuate metabolic disorders in the next generation. In this review, we summarize the existing literature that characterizes how maternal obesity and gestational diabetes mellitus contribute to metabolic and cardiovascular disorders in the offspring. In particular, we focus on animal studies that investigate the molecular mechanisms that are programmed by the gestational environment and lead to disease phenotypes in the offspring. We also review interventional studies that prevent disease with a developmental origin in the offspring.

A low carbohydrate - high fat diet reduces blood pressure in spontaneously hypertensive rats without deleterious changes in insulin resistance

Previous studies reported that diets high in simple carbohydrates could increase blood pressure in rodents. We hypothesized that the converse, a low-carbohydrate/high-fat diet, might reduce blood pressure. Six-week-old spontaneously hypertensive rats (SHR; n = 54) and Wistar-Kyoto rats (WKY; n = 53, normotensive control) were fed either a control diet (C; 10% fat, 70% carbohydrate, 20% protein) or a low-carbohydrate/high-fat diet (HF; 20% carbohydrate, 60% fat, 20% protein). After 10 wk, SHR-HF had lower (P < 0.05) mean arterial pressure than SHR-C (148 ± 3 vs. 159 ± 3 mmHg) but a similar degree of cardiac hypertrophy (33.4 ± 0.4 vs. 33.1 ± 0.4 heart weight/tibia length, mg/mm). Mesenteric arteries and the entire aorta were used to assess vascular function and endothelial nitric oxide synthase (eNOS) signaling, respectively. Endothelium-dependent (acetylcholine) relaxation of mesenteric arteries was improved (P < 0.05) in SHR-HF vs. SHR-C, whereas contraction (potassium chloride, phenylephrine) was reduced (P < 0.05). Phosphorylation of eNOSSer1177 increased (P < 0.05) in arteries from SHR-HF vs. SHR-C. Plasma glucose, insulin, and homoeostatic model of insulin assessment were lower (P < 0.05) in SHR-HF vs. SHR-C, whereas peripheral insulin sensitivity (insulin tolerance test) was similar. After a 10-h fast, insulin stimulation (2 U/kg ip) increased (P < 0.05) phosphorylation of AktSer473 and S6 in heart and gastrocnemius similarly in SHR-C vs. SHR-HF. In conclusion, a low-carbohydrate/high-fat diet reduced blood pressure and improved arterial function in SHR without producing signs of insulin resistance or altering insulin-mediated signaling in the heart, skeletal muscle, or vasculature.

Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring

BackgroundBirth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring. However, the mechanisms involved are unknown. We tested the hypothesis that obesity-associated GDM induces chronic neuroinflammation and disturbs the development of neuronal circuitry resulting in impaired cognitive abilities in the offspring.MethodsIn rats, GDM was induced by feeding dams a diet high in sucrose and fatty acids. Brains of neonatal (E20) and young adult (15-week-old) offspring of GDM and lean dams were analyzed by immunohistochemistry, cytokine assay, and western blotting. Young adult offspring of GDM and lean dams went also through cognitive assessment. Cultured microglial responses to elevated glucose and/or fatty acids levels were analyzed.ResultsIn rats, impaired recognition memory was observed in the offspring of GDM dams. GDM exposure combined with a postnatal high-fat and sucrose diet resulted in atypical inattentive behavior in the offspring. These cognitive changes correlated with reduced density and derangement of Cornu Ammonis 1 pyramidal neuronal layer, decreased hippocampal synaptic integrity, increased neuroinflammatory status, and reduced expression of CX3CR1, the microglial fractalkine receptor regulating microglial pro-inflammatory responses and synaptic pruning. Primary microglial cultures that were exposed to high concentrations of glucose and/or palmitate were transformed into an activated, amoeboid morphology with increased nitric oxide and superoxide production, and altered their cytokine release profile.ConclusionsThese findings demonstrate that GDM stimulates microglial activation and chronic inflammatory responses in the brain of the offspring that persist into young adulthood. Reactive gliosis correlates positively with hippocampal synaptic decline and cognitive impairments. The elevated pro-inflammatory cytokine expression at the critical period of hippocampal synaptic maturation suggests that neuroinflammation might drive the synaptic and cognitive decline in the offspring of GDM dams. The importance of microglia in this process is supported by the reduced Cx3CR1 expression as an indication of the loss of microglial control of inflammatory responses and phagocytosis and synaptic pruning in GDM offspring.

In utero exposure to gestational diabetes mellitus conditions TLR4 and TLR2 activated IL-1beta responses in spleen cells from rat offspring.

Fetal exposure to gestational diabetes mellitus (GDM) is associated with a higher risk of youth-onset insulin resistance and type 2 diabetes. We have previously shown that the rat offspring of GDM dams are insulin resistant when compared to the offspring of lean dams. Since inflammation influences insulin sensitivity, we examined the impact of fetal exposure to GDM on inflammatory responses in the offspring. In rats, we compared inflammatory activity in newborn pups as well as 16week-old young-adult offspring from lean control dams with offspring from high fat and sucrose diet (HFS)-induced GDM dams. To determine whether there are additive effects of exposure to GDM and post-weaning diets, offspring of lean and GDM dams were fed either low fat or HFS diets until 16weeks of age. Plasma levels of interleukin(IL)-1β were elevated in the offspring of GDM dams. To determine whether this was related to immune reactivity, spleen cells from both the newborn and 16week-old offspring were isolated and reactivity to the toll-like receptor activators, pam3CSK4 and lipopolysaccharides were measured over a 72h timeframe. Spleen cells of GDM dams exhibited sustained stimulation of interleukin(IL)-1β and IL-10 production, whereas IL-1β and IL-10 synthesis diminished over time in spleen cells from the offspring of lean dams. Additive effects of GDM exposure and post-weaning HFS diet were not observed, suggesting the effects of GDM on cytokine production are independent of the post-weaning diet. Thus, we conclude that exposure to GDM in utero may condition the immune reactivity of spleen cells.

High-dose metformin (420 mg/kg daily p.o.) increases insulin sensitivity but does not affect neointimal thickness in the rat carotid balloon injury model of restenosis

OBJECTIVE Our laboratory has shown that insulins effect to decrease neointimal thickness after arterial injury is greatly diminished in insulin resistant conditions. Thus, in these conditions, a better alternative to insulin could be to use an insulin sensitizing agent. Metformin, the most commonly prescribed insulin sensitizer, has a cardiovascular protective role. Therefore, the objective of this study was to investigate the potential benefit of metformin on neointimal area after arterial injury in a rat model of restenosis. METHODS Rats fed with either normal or high fat diet and treated with or without oral metformin (420mg/kg daily) underwent carotid balloon injury. Effects of metformin on clamp-determined insulin sensitivity, vessel AMPK (AMP-activated protein kinase) phosphorylation (activation marker) and neointimal area were evaluated. RESULTS Metformin increased insulin sensitivity, but did not affect neointimal thickness in either the normal fat or high fat diet-fed rats. Furthermore, metformin activated AMPK in uninjured but not in injured vessels. Similarly, 10mmol/L metformin inhibited proliferation and activated AMPK in smooth muscle cells of uninjured but not injured vessels, whereas 2mmol/L metformin did not have any effect. CONCLUSION In rats, metformin does not decrease neointimal growth after arterial injury, despite increasing whole body insulin sensitivity.