Ellagic Acid prevents vascular dysfunction in small mesenteric arteries of ovariectomized hypertensive rats.

Cardiovascular diseases rank the top causes of death worldwide, with a substantial increase in women compared to men. Such increase can beexplained by the drastic decrease in 17-ß-estradiol hormone during menopause and associated with endothelium-dependent vascular dysfunction. The current treatments for cardiovascular diseases (e.g., hypertension), are only palliative and therefore, feasible, non-invasive options for preventing further vascular damage are needed. The polyphenol ellagic acid (EA) has risen as a candidate with possible vascular protection properties. This study evaluated the effects of EA in small mesenteric arteries of ovariectomized spontaneously hypertensive rats. Our findings showed that EA oral treatment for 4 weeks preserved vasodilation endothelial-dependent in acetylcholine pre-constricted arteries of spontaneously hypertensive rats to the same extent as 17-ß-estradiol treatment, an effect that was abolished in the presence of the nitric oxide synthase inhibitor L-NitroG-L-Arginine Methyl Ester. Moreover, EA induced vascular nitric oxide release, by increasing both the activitation site phosphorylation and total levels of the endothelial nitric oxide synthase. Finally, EA decreased superoxide anion while increased total levels of the antioxidant enzymes Superoxide Dismutase 2 and catalase. We concluded that EA has vasodilation properties acting via endothelial nitric oxide synthase activation and a potential antioxidant effect by stimulating the Superoxide Dismutase 2-catalase pathway.

Ellagic acid prevents myocardial infarction-induced left ventricular diastolic dysfunction in ovariectomized rats.

Estrogen deficiency is associated with increased oxidative stress, which can contribute to left ventricular diastolic dysfunction (LVDD). We hypothesized that oral treatment with ellagic acid (EA), a potent and natural antioxidant compound, can improve MI-induced LVDD in ovariectomized rats, by reducing the formation of reactive oxygen species. Ovariectomized rats MI-induced LVDD followed by treatment with vehicle (DD) or EA (DD + EA) for 4 weeks. Non-LVDD-induced rats treated with vehicle (S) or EA (S + EA) were used as controls. Left ventricular systolic pressure; left ventricular end-diastolic pressure (LVEDP); maximum rate of pressure rise: +dP/dt and fall: -dP/dt) were evaluated in all animals after treatment. Left ventricle superoxide anion formation was quantified in situ by fluorescence. Phospho-CAMKII, SOD2, catalase, and gp91-phox abundances were evaluated by Western blot analyses. SOD (superoxide dismutase) and catalase activities were measured by spectrophotometry. The results showed that the LVEDP was significantly increased in both DD and DD + EA groups compared to S and S + EA. However, LVEDP in the DD + EA group was significantly decreased compared to DD, indicating an EA-mediated effect. In the DD group, superoxide production and gp91-phox protein abundance were increased while SOD2 abundance was decreased when compared to the S and S + EA groups. An increase in SOD activity was also observed in the DD + EA group. EA treatment reduced CaMKII phosphorylation in the DD + EA group compared to the DD. We concluded that EA treatment attenuated diastolic dysfunction in our experimental model, via reduction of reactive oxygen species and CaMKII activity, indicating EA as a promising natural therapeutic option for cardiac dysfunction.

Exercise training improves vascular reactivity in ovariectomized rats subjected to myocardial infarction.

The aim of this study was to evaluate the effects of exercise training (ET) on the aortic vascular reactivity of ovariectomized and infarcted rats. The animals were divided into 5 groups: Control, Ovariectomized + SHAM sedentary (OVX+SHAMSED), OVX+SHAM and ET (OVX+SHAMET), OVX + Myocardial Infarction sedentary (OVX+MISED), and OVX + MI and ET (OVX+MIET). ET protocol (60 minutes/day, 5x/week) in a motorized treadmill began 15 days after MI and lasted 8 weeks. The endothelium-dependent and endothelium-independent vascular reactivity were evaluated as well as the role of the reactive oxygen species (ROS). Superoxide and nitric oxide (NO) production were analyzed in situ using DHE and DAF-2 fluorescence, respectively. The expression of gp91phox and of the antioxidant enzymes were evaluated by western blotting in the thoracic aorta samples. MI promoted a significant increase in the contractile response and impaired endothelium-mediated relaxation. However, ET prevented the impairment in the vascular reactivity in MI animals. In addition, the protein expression of gp91phox and superoxide production increased and the NO production decreased in the OVX+MISED group but not in the OVX+MIET group. Therefore, ET improves vascular reactivity in MI ovariectomized rats by preventing the increase in the expression of gp91phox and the decrease in the antioxidant enzymes, resulting in a normal ROS and NO production. Thus, ET can be an effective therapeutic strategy for improving the MI-induced vascular alterations in estrogen deficiency condition.

Estrogen Therapy Worsens Cardiac Function and Remodeling and Reverses the Effects of Exercise Training After Myocardial Infarction in Ovariectomized Female Rats.

There is an increase in the incidence of cardiovascular events such as myocardial infarction (MI) after menopause. However, the use of estrogen therapy (E2) remains controversial. The aim of this study was to evaluate the effects of E2, alone and combined with exercise training (ET), on cardiac function and remodeling in ovariectomized (OVX) rats after MI. Wistar female rats underwent ovariectomy, followed by MI induction were separated into five groups: S; MI; MI+ET; MI+E2; and MI+ET+E2. Fifteen days after MI or sham surgery, treadmill ET and/or estrogen therapy [17-ß estradiol-3-benzoate (E2), s.c. three times/week] were initiated and maintained for 8 weeks. After the treatment and/or training period, the animals underwent cardiac hemodynamic evaluation through catheterization of the left ventricle (LV); the LV systolic and diastolic pressures (LVSP and LVEDP, respectively), maximum LV contraction and relaxation derivatives (dP/dt+ and dP/dt-), and isovolumic relaxation time (Tau) were assessed. Moreover, histological analyses of the heart (collagen and hypertrophy), cardiac oxidative stress [advanced oxidation protein products (AOPPs)], pro- and antioxidant protein expression by Western blotting and antioxidant enzyme activity in the heart were evaluated. The MI reduced the LVSP, dP/dt+ and dP/dt- but increased the LVEDP and Tau. E2 did not prevent the MI-induced changes in cardiac function, even when combined with ET. An increase in the dP/dt+ was observed in the E2 group compared with the MI group. There were no changes in collagen deposition and myocyte hypertrophy caused by the treatments. The increases in AOPP, gp91-phox, and angiotensin II type 1 receptor expression induced by MI were not reduced by E2. There were no changes in the expression of catalase caused by MI or by the treatments, although, a reduction in superoxide dismutase (SOD) expression occurred in the groups subjected to E2 treatment. Whereas there were post-MI reductions in activities of SOD and catalase enzymes, only that of SOD was prevented by ET. Therefore, we conclude that E2 therapy does not prevent the MI-induced changes in cardiac function and worsens parameters related to cardiac remodeling. Moreover, E2 reverses the positive effects of ET when used in combination, in OVX infarcted female rats.