Exercise modulates the aortic renin-angiotensin system independently of estrogen therapy in ovariectomized hypertensive rats.

The renin-angiotensin-system is an important component of cardiovascular control and is up-regulated under various conditions, including hypertension and menopause. The aim of this study was to evaluate the effects of swimming training and estrogen therapy (ET) on angiotensin-II (ANG II)-induced vasoconstriction and angiotensin-(1-7) [ANG-(1-7)]-induced vasorelaxation in aortic rings from ovariectomized spontaneously hypertensive rats. Animals were divided into Sham (SH), Ovariectomized (OVX), Ovariectomized treated with E2 (OE2), Ovariectomized plus swimming (OSW) and Ovariectomized treated with E2 plus swimming (OE2+SW) groups. ET entailed the administration of 5µg of 17ß-Estradiol three times per week. Swimming was undertaken for sixty minutes each day, five times per week. Both, training and ET were initiated seven days following ovariectomy. Forty-eight hours after the last treatment or training session, the animals' systolic blood pressures were measured, and blood samples were collected to measure plasma ANG II and ANG-(1-7) levels via radioimmunoassay. In aortic rings, the vascular reactivity to ANG II and ANG-(1-7) was assessed. Expression of ANG-(1-7) in aortic wall was analyzed by immunohistochemistry. The results showed that both exercise and ET increased plasma ANG II levels despite attenuating systolic blood pressure. Ovariectomy increased constrictor responses to ANG II and decreased dilatory responses to ANG-(1-7), which were reversed by swimming independently of ET. Moreover, it was observed an apparent increase in ANG-(1-7) content in the aorta of the groups subjected to training and ET. Exercise training may play a cardioprotective role independently of ET and may be an alternative to ET in hypertensive postmenopausal women.

Pomegranate peel extract attenuates oxidative stress by decreasing coronary angiotensin-converting enzyme (ACE) activity in hypertensive female rats.

Based on the antioxidant properties of pomegranate, this study was designed to investigate the effects of pomegranate peel extract on damage associated with hypertension and aging in a spontaneously hypertensive rat (SHR) model. The influence of pomegranate consumption was examined on systolic blood pressure (SBP), angiotensin-converting enzyme (ACE) coronary activity, oxidative stress, and vascular morphology. Four- or 28-wk-old SHR model rats were treated for 30 d, with terminal experimental animal age being 8 and 32 wk, respectively, with either pomegranate extract (SHR-PG) or filtered water (SHR). Data showed significant reduction in SBP and coronary ACE activity in both age groups. The levels of superoxide anion, a measure of oxidative stress, were significantly lower in animals in the SHR-PG group compared to SHR alone. Coronary morphology demonstrated total increases in vascular wall areas were in the SHR group, and pomegranate peel extract diminished this effect. Pomegranate peel extract consumption conferred protection against hypertension in the SHR model. This finding was demonstrated by marked reduction in coronary ACE activity, oxidative stress, and vascular remodelling. In addition, treatment was able to reduce SBP in both groups. Evidence indicates that the use of pomegranate peel extract may prove beneficial in alleviating coronary heart disease.

The Environmental Pollutant Tributyltin Chloride Disrupts the Hypothalamic-Pituitary-Adrenal Axis at Different Levels in Female Rats.

Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function.

Tributyltin chloride leads to adiposity and impairs metabolic functions in the rat liver and pancreas.

Tributyltin chloride (TBT) is an environmental contaminant used in antifouling paints of boats. Endocrine disruptor effects of TBT are well established in animal models. However, the adverse effects on metabolism are less well understood. The toxicity of TBT in the white adipose tissue (WAT), liver and pancreas of female rats were assessed. Animals were divided into control and TBT (0.1 µg/kg/day) groups. TBT induced an increase in the body weight of the rats by the 15th day of oral exposure. The weight gain was associated with high parametrial (PR) and retroperitoneal (RP) WAT weights. TBT-treatment increased the adiposity, inflammation and expression of ERα and PPARγ proteins in both RP and PR WAT. In 3T3-L1 cells, estrogen treatment reduced lipid droplets accumulation, however increased the ERα protein expression. In contrast, TBT-treatment increased the lipid accumulation and reduced the ERα expression. WAT metabolic changes led to hepatic inflammation, lipid accumulation, increase of PPARγ and reduction of ERα protein expression. Accordingly, there were increases in the glucose tolerance and insulin sensitivity tests with increases in the number of pancreatic islets and insulin levels. These findings suggest that TBT leads to adiposity in WAT specifically, impairing the metabolic functions of the liver and pancreas.

Mononuclear cell therapy reverts cuff-induced thrombosis in apolipoprotein E-deficient mice.

BACKGROUND: Stem/progenitor cell-based therapy has successfully been used as a novel therapeutic strategy for vascular diseases triggered by endothelial dysfunction. The aim of this study was to investigate the effects of mononuclear cell (MNC) therapy in situ on carotid cuff-induced occlusive thrombus in the apolipoprotein E knockout (apoE-/-) mouse. METHODS: Spleen-derived MNCs were isolated from green fluorescent protein (GFP)-transgenic mice for cell treatment. A cuff-induced thrombus model was produced by placing a nonconstrictive silastic collar around the left common carotid artery in 20-week-old female apoE-/- mice. After 10 days, the cuff was removed, and the animals received in situ MNCs (Cuff-MNC) or vehicle (Cuff-Vehicle) and were compared with sham-operated animals (Sham). RESULTS: The histological analysis showed that the MNC treatment reverted occlusive thrombus formation compared to the vehicle and the vessel lumen area to that observed in the Sham group (MNC, 50 ± 4; Vehicle, 20 ± 4; Sham, 55 ± 2 x10³ µm²; p < 0.01). The animals that underwent the carotid cuff placement developed compensatory vessel enlargement, which was reduced by the MNC therapy. In addition, the treatment was able to reduce superoxide anion production, which likely contributed to the reduced apoptosis that was observed. Lastly, the immunofluorescence analysis revealed the presence of endothelial progenitor cells (EPCs) in the carotid endothelia of the apoE-/- mice. CONCLUSION: In situ short-term MNC therapy was able to revert cuff-induced occlusive thrombi in the carotid arteries of apoE-/- mice, possibly through the homing of EPCs, reduction of oxidative stress and decreased apoptosis.

Mononuclear cell therapy attenuates atherosclerosis in apoE KO mice.

BACKGROUND: Recent studies have highlighted the potential of cell therapy for atherosclerosis. The aim of this study was to evaluate the effects of mononuclear cell (MNC) therapy on the development of atherosclerotic lesions in the apolipoprotein E knockout (apoE KO) mouse. METHODS: We investigated vascular lipid deposition, vascular remodeling, oxidative stress, and endothelial nitric oxide synthase (eNOS) expression in apoE KO mice treated with spleen MNCs isolated from lacZ transgenic mice (apoE KO-MNC) for 8 weeks compared to untreated control mice (apoE KO). RESULTS: Histological analysis of aortas showed a significant reduction in the lipid deposition area in apoE KO-MNC mice compared to apoE KO mice (0.051 ± 0.004 vs 0.117 ± 0.016 mm², respectively, p < 0.01). In addition, vessel morphometry revealed that MNC therapy prevented the outward (positive) remodeling in apoE KO mice that is normally observed (apoE KO-MNC: 0.98 ± 0.07 vs apoE KO: 1.37 ± 0.09), using wild-type mice (C57BL/6J) as a reference. ApoE KO-MNC mice also have reduced production of superoxide anions and increased eNOS expression compared to apoE KO mice. Finally, immunohistochemistry analysis revealed a homing of endothelial progenitor cells (EPCs) in the aortas of apoE KO-MNC mice. CONCLUSION: MNC therapy attenuates the progression of atherosclerosis in the aortas of apoE KO mice. Our data provide evidence that the mechanism by which this attenuation occurs includes the homing of EPCs, a decrease in oxidative stress and an upregulation of eNOS expression.

Cardiac and vascular changes in elderly atherosclerotic mice: the influence of gender.

BACKGROUND: Although advanced age is considered a risk factor for several diseases, the impact of gender on age-associated cardiovascular diseases, such as atherosclerotic processes and valvular diseases, remains not completely clarified. The present study was designed to assess aortic valve morphology and function and vascular damage in elderly using the apolipoprotein E knockout (ApoE KO) mouse. Our hypothesis was that advanced age-related cardiovascular changes are aggravated in atherosclerotic male mice. METHODS: The grade (0 to 4) of aortic regurgitation was evaluated through angiography. In addition, vascular lipid deposition and senescence were evaluated through histochemical analyses in aged male and female ApoE KO mice, and the results were compared to wild-type C57BL/6J (C57) mice. RESULTS: Aortic regurgitation was observed in 92% of the male ApoE KO mice and 100% of the male C57 mice. Comparatively, in age-matched female ApoE KO and C57 mice, aortic regurgitation was observed in a proportion of 58% and 53%, respectively. Histological analysis of the aorta showed an outward (positive) remodeling in ApoE KO mice (female: 1.86 ± 0.15; male: 1.89 ± 0.68) using C57 groups as reference values. Histochemical evaluation of the aorta showed lipid deposition and vascular senescence only in the ApoE KO group, which were more pronounced in male mice. CONCLUSION: The data show that male gender contributes to the progression of aortic regurgitation and that hypercholesterolemia and male gender additively contribute to the occurrence of lipid deposition and vascular senescence in elderly mice.