Efeitos cardíacos produzidos pela ovariectomia em ratas diabéticas

Abstract

The present study evaluated the hypothesis that estrogen depletion may exarcebate the cardiac deleterious effect induced by diabetes in two different animal models: Sprague-Dawley (SD) and mRen2.Lewis (mRen), a strain that exhibits greater estrogen sensitivity. Material and Methods: The experimental design was similar for both animal models: ovariectomy (OVX) was performed between 10-11 weeks of age and diabetes subsequently induced one week later with a single dose of streptozotocin (STZ; 65 mg/kg) for 4 weeks. Our study was divided into two experiments: Experiment I (results obtained with SD rats) and Experiment II (results obtained with mRen rats). In Experiment I, part of diabetic animals received exogenous insulin (INS) in order to restore the hyperglycemic effects. SD rats were divided into 6 groups: CTL, STZ, OVX, OVX-STZ, STZ + INS, OVX-STZ + INS. In Experiment II, rats were divided into 4 groups: mRen CTL; mRen STZ; mRen OVX and mRen OVX-STZ. The potential beneficial cardiovascular effects of G-1, a selective agonist of a novel estrogen receptor GPR30, was evaluated in insulin and estrogen depleted mRen.Lewis rats. Hemizygous littermates were divided into 3 groups: CTL, OVX-STZ + vehicle and OVX-STZ + G1. Results: Experiment I - STZ rats showed an impaired systolic function (reduced ejection fraction and fractional shortening), increased ejection time, reduced relative wall thickness and increased cardiac fibrosis. Depletion of estrogen did not change the diabetic deleterious effects on cardiac structure and function in OVX-STZ rats. Moreover, insulin replacement restored cardiac changes observed in rats that had concomitant diabetes and estrogen depletion (OVX + STZ-INS), suggesting that diabetes has a predominant effect on cardiac structure and function than ovariectomy; Experiment II: mRen OVX-STZ rats showed increased blood pressure levels, collagen deposition in the heart tissue and cardiomyocyte diameter when compared to rats that underwent ovariectomy or induction of diabetes alone. These changes were accompanied by an increased cardiac expression of AT1 receptor and a reduced cardiac expression of eNOS associated with lower NO levels in the heart. These effects were also observed in mRen STZ rats however only mRen OVX-STZ rats had increased AT1 to Mas receptor ratio, increased amount of Ang II remained in the left ventricle and increase in cardiac Nox2 expression. Thus, our study suggests that the phenotypic changes observed in OVX STZ rats are due to an additional effect of estrogen depletion and diabetes on the RAS and reactive oxygen species generation. Chronic treatment with G-1 slightly decreased elevated blood pressure and incidence of microinfarcts in diabetic ovariectomized mRen rats. Furthermore, cardiac expression of eNOS protein increased in G-1 treated rats. In contrast, G-1 did not affect cardiac AT1 receptor expression. Conclusion: the present study suggests that selective activation of a novel GPR30 receptor may prevent cardiac injury in estrogen and insulin depleted mRen2.Lewis rats by reducing blood pressure and preserving eNOS pathway.