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

Abstract

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-β 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.

Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress

“…Kauser et al [170] first found that there were gender differences in the production and release of NO, and the release of NO in the aorta of female rats was higher than that of males. Estrogen maintains the bioavailability of NO by increasing the expression of eNOS mRNA and protein, thus increasing the production of NO in endothelial cells and vascular smooth [167,[184][185][186][187][188][189][190] Estrogen restored antioxidant enzymes GPX1 and GPX4 expression levels Oxidative stress balance was maintained [158,181,189] Estrogen increased the expression of the glutathione rate-limiting enzyme γ-glutamylcysteine synthetase Oxidative stress balance was maintained [168,190,191] Estrogen maintained the bioavailability of NO by increasing the expression of eNOS mRNA and protein…”

Estrogen Receptors: Therapeutic Perspectives for the Treatment of Cardiac Dysfunction after Myocardial Infarction

“…Whereas short-term administration of E2 after MI would seem harmful, as it increases infarction area in OVX-MI rats, long-term treatment with E2 normalizes ventricular wall tension and chamber dimension in these animals by regulating the endothelin system and promoting increased survival [ 41 ]. Recent work has demonstrated that long-term E2 administration to OVX-MI rats failed to prevent cardiac dysfunction and remodeling [ 67 ]. Interestingly, OVX rats subjected to ischemia-reperfusion (I/R) present significantly decreased post-ischemic recovery of left ventricular function and increased MI extension, and these deleterious effects were avoided by E2 [ 68 ].…”

Efeitos do Exercício Aeróbico Tardio na Remodelação Cardíaca de Ratos com Infarto do Miocárdio Pequeno

“…8,10,33 Apenas alguns pesquisadores analisaram os efeitos do exercício no coração de ratos com IM pequeno. 35,36 Ao iniciarem o exercício dentro de quatro semanas após a indução do IM, esses autores observaram efeitos benéficos do exercício físico. 35,36 Neste estudo, mostramos pela primeira vez que o exercício aeróbico tardio, iniciado três meses após o IM, quando a remodelação cardíaca está estável, atenua as alterações da geometria cardíaca em ratos com pequeno infarto.…”

“…35,36 Ao iniciarem o exercício dentro de quatro semanas após a indução do IM, esses autores observaram efeitos benéficos do exercício físico. 35,36 Neste estudo, mostramos pela primeira vez que o exercício aeróbico tardio, iniciado três meses após o IM, quando a remodelação cardíaca está estável, atenua as alterações da geometria cardíaca em ratos com pequeno infarto. Nosso estudo, portanto, reforça o conceito de benefício potencial da reabilitação cardíaca após síndromes coronarianas agudas, independentemente do grau de lesão cardíaca.…”