Abstract-Angiotensin type 2 receptor-mediated effects of angiotensin II appear to counteract many of the effects mediated via the angiotensin type 1 receptor. Compound 21 (C21), a selective angiotensin type 2 receptor agonist, has demonstrated beneficial effects on cardiac function after myocardial infarction in rodents. We hypothesized that C21 alone or in combination with an angiotensin type 1 receptor antagonist would blunt the development of hypertension and vascular damage in stroke-prone spontaneously hypertensive rats. Six-week-old stroke-prone spontaneously hypertensive rats received C21 (1 mg/kg per day), the angiotensin type 1 receptor antagonist losartan (10 mg/kg per day), C21 plus losartan, or vehicle PO for 6 weeks. Systolic blood pressure was lower in losartan and C21-losartan combination groups (PϽ0.001). Endotheliumdependent relaxation was enhanced (PϽ0.001) in the C21-losartan combination group at lower acetylcholine concentrations. C21 or C21-losartan combination reduced vascular stiffness, aortic medial and myocardial interstitial collagen content, and aortic fibronectin (PϽ0.05). C21 and losartan decreased the expression of 2 genes associated with cardiac hypertrophy, myosin heavy chain-␤ (myh7) by 30 to 50%, and ␣-skeletal muscle actin by 30% to 35% (PϽ0.05). C21-losartan combination caused an additional 40% reduction in myh7 compared with C21 (PϽ0.01). Aortic superoxide generation was reduced equally by the 3 treatments (PϽ0.001). Monocyte/macrophage infiltration in the aorta and kidney (PϽ0.001) and T-lymphocyte infiltration in the renal cortex (PϽ0.05) were lowered similarly by the 3 treatments. These data suggest that C21 alone or in combination with losartan may improve endothelial function and vascular composition and mechanics by reducing oxidative stress, collagen content, fibronectin, and inflammatory cell infiltration in stroke-prone spontaneously hypertensive rats. hronic hypertension results in vascular remodeling and inflammation, endothelial dysfunction, and accelerated development of atherosclerosis. 1,2 Of the many factors implicated in hypertensive vascular remodeling, angiotensin (Ang) II, the main effector hormone of the renin-Ang-aldosterone system, seems to be one of the most important. 3 Ang II exerts its effects by binding to 2 membrane-bound, G proteincoupled receptors, Ang II type 1 (AT 1 R) and type 2 receptors (AT 2 R). Most well-known effects of Ang II that contribute to unfavorable vascular remodeling and consequent hypertensive complications are mediated via AT 1 R, whereas those exerted via AT 2 R are less well known and appear to counteract many of its effects exerted via AT 1 R. 4,5 AT 2 Rmediated effects seem to exert vasculoprotective actions via vasodilation, NO production, 6 -8 and apoptosis and inhibition of growth and fibrosis. 5,9,10 Beneficial vascular effects of AT 1 R blockade have been at least partially attributed to unopposed AT 2 R stimulation. 7,11,12

Emerging data indicate a correlation between gut microbial composition and cardiovascular disease including hypertension. The host’s diet greatly affects microbial composition and metabolite production. Short chain fatty acids (SCFAs) are products of microbial fermentation, which can be utilized by the host. It has been suggested that SCFAs play a pivotal role as mediators in a microbiome host: microbial interactions occur in health and disease. The aim of this study was to evaluate the effect of a high salt diet (HSD) on microbial variation and to determine whether this effect is accompanied by an alteration in fecal SCFAs. To this end, Dahl salt-sensitive rats were divided into two groups (n = 10 each): (A) Control: fed regular chow; and (B) Fed HSD. High-throughput pyrosequencing of the 16S rRNA amplicon sequencing was used for microbiome characterizing. Chromatography-mass spectrometry was used to measure the levels of SCFAs: acetic acid, propionic acid, butyric acid, and isobutyric acid in fecal samples. Differences in microbial composition were noted between groups. Principal Coordinate Analysis (PCoA) principal coordinate 1 (PC1) primarily separated controls from the HSD. Four taxa displayed significant differences between HSD and controls. Taxa from the Erwinia genus, the Christensenellaceae and Corynebacteriaceae families, displayed an increased abundance in HSD versus control. In contrast, taxa from the Anaerostipes genus displayed a decreased abundance in HSD. We were able to identify seven unique taxa that were significantly associated with blood pressure. There was a significant difference in fecal acetic acid, as well as propionic and isobutyric acid, but not in the butyric acid composition between groups. Adding salt to a diet impacts the gut’s microbial composition, which may alter fecal SCFA production.

SummaryThere is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD‐like model mice on high‐AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle‐linked disease epidemic.

Inflammation plays an important role in the pathogenesis of hypertension. Innate and adaptive immune response may contribute to this process. The mechanisms implicating immune response in hypertension are still elusive. To date, the evidence originates in three major areas of data: cytokine production, central nervous system (CNS) stimulation, and kidney damage. The cytokine microenvironment can become proinflammatory and propagate low-grade inflammation, which may contribute to vascular injury and end-organ damage in hypertension. In addition, stimulation of the CNS by some stimuli (e.g., angiotensin II) causes mild hypertension that may modulate peripheral immune responses leading to aggravation of blood pressure elevation. The immune response can induce kidney injury and also interfere with sodium excretion, further contributing to elevation of blood pressure. The purpose of this review is to discuss recent data regarding the contribution of the different immune cell subsets and their response and mechanism of action in promoting hypertension and target-organ damage.

Melatonin secretion decreased in fructose fed rats that developed hypertension. Administration of melatonin blunted this BP rise. These data suggested that melatonin plays a role in the pathogenesis of hypertension in rats with metabolic syndrome.

Inducible Pparγ inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPARγ in angiotensin II-induced vascular injury.

Abstract-We recently showed that T regulatory lymphocytes (Treg), which are immune suppressors of inflammatory responses, play a role blunting the development of hypertension-induced injury. Treg are unchanged or decreased in children with metabolic syndrome, and therefore, their role in metabolic syndrome remains unclear. We hypothesized that Treg number or function would be depressed in a high-fructose diet-induced metabolic syndrome-like model in rats. Sprague-Dawley rats were fed normal chow or a high-fructose diet for 5 weeks. The high-fructose diet-induced a 3.8-fold increase in plasma triglycerides and a 14% reduction in high-density lipoprotein cholesterol (P<0.001). The high-fructose diet increased reactive oxygen species in aorta and periaortic adipose tissue 2.8-fold (P<0.05), and reduced nicotinamide adenine dinucleotide phosphate oxidase activity 1.9-fold in aorta, and 2.5-fold in the heart (P<0.05). It also increased plasma nitric oxide metabolite levels 6.4-fold (P<0.001). Western blots showed that the high-fructose diet increased ≥2.3-fold vascular and in platelet endothelial cell adhesion molecule 1 in aorta (P<0.01). It did not affect monocyte/macrophage aortic infiltration but caused a 2.4-fold increase in collagen deposition in the aortic media (P<0. 01 FoxP3+ cells was observed in children with metabolic syndrome (2.5 versus 3.1%). 15To determine the role of Treg in the metabolic syndrome, vascular oxidative stress and inflammation and the number and function of Treg were studied in high-fructose diet-fed SpragueDawley rats, a well-established model mimicking some features of the western diet-induced metabolic syndrome. 16,17 These rats exhibit hypertension, insulin resistance, and abnormal lipid profile resembling the human metabolic syndrome better than a monogenic model. We hypothesized that vascular oxidative stress and inflammation and changes in the immune response, including Treg activity and response, participate in the mechanisms leading to the metabolic syndrome. Materials and MethodsAdditional materials and methods are described in the online-only Data Supplement. Experimental DesignEight-week-old Sprague-Dawley male rats (Harlan Laboratories, Indianapolis, IN) were fed a high-fructose diet (TD.89247, Harlan Laboratories) composed of 60% fructose, 21% protein, 5% fat, 8% cellulose, and standard vitamins and mineral mix or normal chow diet (control) for 5 weeks. Systolic BP (SBP) was measured by the tailcuff method after 4 weeks on the diet. SBP was also determined by telemetry together with heart rate and animal activity every 5 minutes for 10 seconds for 2 consecutive days at baseline and at the end of every week during the 5 weeks of treatment. Three days before the end of the protocol, blood was collected from the saphenous vein on heparin for triglycerides, and high-density lipoprotein cholesterol was determined after 5 hours of fasting. At the end of the protocol, body weight was evaluated, and rats were anesthetized with 3% isoflurane mixed with O 2 at 1 L/min (depth of ane...

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