Effects of hypoestrogenism and/or hyperaldosteronism on myocardial remodeling in female mice

Abstract

We investigated the potential adverse effects of hyperaldosteronism and/or hypoestrogenism on cardiac phenotype, and examined their combined effects in female mice overexpressing cardiac aldosterone synthase (AS). We focused on some signaling cascades challenging defensive responses to adapt and/or to survive in the face of double deleterious stresses, such as Ca2+‐homeostasis, pro/anti‐hypertrophic, endoplasmic reticulum stress (ER stress), pro‐ or anti‐apoptotic effectors, and MAP kinase activation, and redox signaling. These protein expressions were assessed by immunoblotting at 9 weeks after surgery. Female wild type (FWT) and FAS mice were fed with phytoestrogen‐free diet; underwent ovariectomy (Ovx) or sham‐operation (Sham). Ovx increased gain weight and hypertrophy index. Transthoracic echocardiograghy was performed. Both Ovx‐induced heart rate decrease and fractional shortening increase were associated with collagen type III shift. Cardiac estrogen receptor (ER α, ER β) protein expression levels were downregulated in Ovx mice. Hypoestrogenism increased plasma aldosterone and MR protein expression in FAS mice. Both aldosterone and Ovx played as mirror effects on up and downstream signaling effectors of calcium/redox homeostasis, apoptosis, such as concomitant CaMKII activation and calcineurin down–regulation, MAP kinase inhibition (ERK1/2, p38 MAPK) and Akt activation. The ratio Bcl2/Bax is in favor to promote cell survivor. Finally, myocardium had dynamically orchestrated multiple signaling cascades to restore tolerance to hostile environment thereby contributing to a better maintenance of Ca2+/redox homeostasis. Ovx‐induced collagen type III isoform shift and its upregulation may be important for the biomechanical transduction of the heart and the recovery of cardiac function in FAS mice. OVX antagonized aldosterone signaling pathways.

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice

“…11 Estradiol treatment in these OVX-DS/obese rats attenuated hypertension and obesity but did not improve heart function because of exacerbated LV fibrosis and diastolic dysfunction, probably mediated by MR activation. 11 On the other hand, in mice with ovariectomy, Rouet-Benzineb et al measured reduced LV protein expression of oestrogen receptor ER-α and ER-β while showing augmented protein expression of cardiac MR. 12 Although a theoretical enhancement of ER activity could be hypothesized at least via indirect mechanisms, for example, counter-regulation of endogenous steroid hormone release by an unselective receptor profile as demonstrated for spironolactone 44 or recruitment of the transcriptional co-activator steroid receptor coregulatory-1 (Src-1), which is shared by most steroid hormone receptors, we have no reason to believe that such indirect mechanisms apply to the benefits of finerenone in the current study. Indeed, (i) finerenone does not have any detectable affinity for both ERα and ERβ, 45 and (ii) finerenone has been demonstrated to act as an inverse agonist for Src-1 recruitment (i.e.…”

“…On the other hand, in mice with ovariectomy, Rouet‐Benzineb et al . measured reduced LV protein expression of oestrogen receptor ER‐α and ER‐β while showing augmented protein expression of cardiac MR 12 …”

“…In mice, Rouet‐Benzineb et al . showed that preserved FS after 2 months of ovariectomy concealed increased expressions of proteins involved in Ca 2+ reuptake, that is, phosphorylated Thr 17 phospholamban (p‐CaMKII) and the phosphatase calcineurin 12 . Moreover, regarding myocardial stiffness, Farré et al .…”

“…28 In mice, Rouet-Benzineb et al showed that preserved FS after 2 months of ovariectomy concealed increased expressions of proteins involved in Ca 2+ reuptake, that is, phosphorylated Thr 17 phospholamban (p-CaMKII) and the phosphatase calcineurin. 12 Moreover, regarding myocardial stiffness, Farré et al proposed that a reduction measured in LV strips after 6 months of ovariectomy in mice aged 9 months was due to cardiomyocytes rather than extracellular matrix, because the difference between OVX and controls disappeared in decellularized strips. 29 These publications argue in favour of the importance of the intracellular component in ovariectomy-induced diastolic dysfunction that we showed to be ameliorated in OVX mice treated with finerenone.…”

“…Among proposed mechanisms, clinical and basic research has implicated an activation of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of diastolic dysfunction after menopause. 9 After ovariectomy-induced post-menopausal conditions, increased expression of cardiac local RAAS components has been reported in rodents, including angiotensin II 10 in rats and MR in rats 11 and mice, 12 with an increase in plasma aldosterone that was evidenced in rats. 10,13 In obese mice, endothelial MR has been proposed as a player driving sex differences in the dysfunction of resistance arteries.…”