Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats

Abstract

Background/aim:Estrogen deficiency induces myocardial contractile dysfunction and increases cardiovascular disease risk. However, the mechanism underlying this response is unclear. Our aim was to investigate whether AT₁receptor blockade would prevent ovariectomy-induced myocardial contractile dysfunction. Methods: Female rats (8 weeks old, 280 g) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with losartan (OVX + LOS, 15 mg/kg, s.c., in 0.9 % NaCl), placebo (OVX), estrogen replacement (OVX + E2, 1 mg/ kg, once a week, i.m.) and SHAM for 58 days. Results: Losartan and estrogen treatment 1) prevented ovariectomy-induced weight gain and slight hypertrophy, 2) restored the positive inotropic responses to Ca²⁺ and isoproterenol in the isolated papillary muscle in the OVX group, 3) prevented the reduction in SERCA2a levels and the increase in phospholamban (PLB) expression in the OVX group, 4) abolished the increase in superoxide anion that was increased in the OVX group, and 5) normalized the increase in p22^phox expression after ovariectomy. Estrogen treatment but not losartan restored the increase in serum angiotensin converting enzyme activity in the OVX group. Conclusion: This study demonstrated that myocardial contractile dysfunction induced by ovariectomy and expression of key Ca²⁺-handling proteins were prevented by losartan treatment and that AT₁receptor activation is involved in this response.

Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR

“…Nonetheless, in previous work using the mRen2.Lewis hypertensive rat, we showed increased cardiac Ang II levels after estrogen loss and this was directly related to cardiac chymase expression (Wang et al, 2013). Moreover, Ribeiro et al (2012) reported that AT1 receptor blockade prevented ovariectomy-induced myocardial contractile dysfunction in normotensive Wistar rats. The increased cardiac Ang II immunoreactivity found in LV tissue of OVX versus gonadal-intact WKY and SHR rats suggest that intracellular Ang II production from chymase, within cardiomyocytes, is likely partially involved in the anatomic and functional derangements of the LV after estrogen loss.…”

The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview

“…Ovariectomy induces myocardial contractile dysfunction in female rats, 97 suggesting that estrogen plays an important role in cardiac contraction. Significant gender differences in the parameters of cardiac excitation-contraction (E-C) coupling exist between male and female hearts and cultured myocytes.…”

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

“…However, in other studies, no change was observed in the expression of NCX expression in both oestrogen treatment and OVX animals . Although oestrogen decreased the expression of PLB, and OVX increased its expression, no change in expression was found in other reports . On the other hand, oestrogen downregulated the RyR expression, while in other reports both OVX and oestrogen treatments had no effect on RyR expression .…”

“…These studies were carried out in different animal species, disease models, tissue/cell types, age groups, in vivo and ex vivo and using different oestrogen types. Moreover, the observed changes in protein expression due to OVX were reversed by oestrogen replacement . This implies that the discrepancies between some of the results could be a result of the experimental variations, and hence, head‐to‐head comparisons might not be possible.…”