Estrogen Receptor Activation—Good, Aldosterone Receptor Blockade—Beneficial, Communication Between Receptors…Priceless
Steroid receptors are essentially transcription factors. When estrogens activate estrogen receptors (ERs) and aldosterone activates the mineralocorticoid receptor (MR) these steroid-receptor complexes enter the nucleus. On entry, these complexes bind to their respective response elements leading to the regulation of gene expression. This transcriptional regulation of key genes in target tissues yields relevant reproductive and endocrine functions. Because ER and MR are expressed in cardiac myocytes, fibroblasts, and vascular cells, genes essential to cardiovascular function and cardiovascular pathophysiology are regulated by aldosterone and estrogens.1,2
The consensus from research on cardiovascular tissue focusing on estrogens is that ER activation is beneficial. Specifically, ER activation has been suggested to attenuate mitogen-activated protein kinase growth signaling in response to pressure overload, increase endothelial NO synthesis, reduce vascular cell proliferation, and decrease endothelin expression.1 In addition, blunted hypertrophic responses in female mice lacking the ryanodine receptor-associated protein and guanylyl cyclase-A receptor suggest that estrogens may attenuate calcineurin/nuclear factor-activated T-cell signaling and or mediate downstream signaling in the atrial natriuretic peptide-guanylyl cyclase cascade.3,4 Whereas ER activation with specific and nonspecific estrogen agonists produce molecular responses favoring cardiovascular protection, the contrary has been demonstrated with studies examining MR activation.2
The deleterious nature of excessive MR activation was evidenced by the Randomized Aldactone Evaluation Study.2 The Randomized Aldactone Evaluation Study demonstrated improved outcomes in patients with heart failure being treated with the MR antagonist spironolactone. The rationale for the use of spironolactone in heart failure was based on the ability of aldosterone, via the genomic pathway, to initiate cardiac fibrosis and inflammation in animal models.2 Although the Randomized Aldactone Evaluation Study improved our understanding of the pathophysiology of heart failure and its therapeutic strategies, studies demonstrating myocardial aldosterone synthesis and the absence of fibrosis in normal rat hearts containing elevated myocardial aldosterone concentrations raised questions regarding direct actions of aldosterone in the heart.5 Particularly, in the continuum between health and disease, it was unclear how an essential steroid vital to normal cardiovascular function and pressure-volume regulation could become so deleterious. This notion prompted speculation that the myocardium was protected from the physiological effects of aldosterone and that loss of this protection gives way to the pathological aldosterone-MR-mediated actions. To this end, the work by Arias-Loza et al,6 appearing in this issue of Hypertension, presents data that may provide an initial explanation of how ER activation may protect the cardiovascular system from the deleterious actions of excessive MR activation.
Arias-Loza et al6 demonstrated that both α and β ER agonists protect the cardiovascular system against MR-mediated hypertension, cardiac hypertrophy, and vascular fibrosis in rats chronically infused with aldosterone.6 Using 2D gel electrophoresis and mass spectroscopy, expression profiles were identified for ERα and ERβ agonists. Activation of both ER subtypes prevented MR-mediated osteopontin and neurabin II expression. The blunting of neurabin II by ER agonists is significant in the context that this protein targets protein phosphatase I to the actin cytoskeleton7 and that overexpression of protein phosphatase I leads to cardiac dilatation, decrease phospholamban phosphorylation, impaired calcium sequestering, and decreased β-adrenergic responsiveness.8 Therefore, because ER activation blunts a protein phosphatase I targeting protein, this finding could potentially account for the observed gender disparities in the development of cardiac dilatation and systolic dysfunction.9 In addition, demonstrating that both ER subtypes attenuated osteopontin expression, reduced aortic media thickening, and reduced perivascular fibrosis, the therapeutic value of nonfeminizing ER agonists in cardiovascular disease warrants future investigation.
With regard to the preservation of cardiac function, ERα agonists were shown to prevent the downregulation of α-myosin heavy chain (MHC), an MHC isoform that correlates positively with cardiac performance. Although the human heart primarily possesses β-MHC, this finding is germane to the human heart, because nonfailing human hearts are believed to contain between 5% and 10% α-MHC compared with 0% to 2% present in failing heart.10 Moreover, demonstrating that ER activation blunts α- to β-MHC switching in response to hypertension could potentially explain the greater hypertrophic reserve observed in female rodent hearts in response to pressure overload. The conversion of α- to β-MHC represents a compensatory occurrence during hypertension, because the slower ATPase velocity associated with β-MHC is more suitable for generating force against a higher afterload compared with the faster ATPase velocity associated with α-MHC.10 Therefore, one may speculate whether the larger hypertrophic reserve observed in female rodent hearts occurs to counterbalance the limited α- to β-MHC isoform conversion associated with ER activation.
Although the work by Arias-Loza et al10 contributes to our understanding of communication between ER and MR and the protection ER has against excessive MR activation, these findings raise new questions. In particular, why has estrogen replacement therapy been less than favorable? Could a possible explanation be related to the positive inotropic actions demonstrated by estrogen? Albeit conjecture, one could speculate that, before menopause, estrogens provide a cyclic cardiovascular challenge, which may condition the heart in a manner similar to aerobic exercise conditioning. This conditioning, in turn, could potentially explain the lower incidences of cardiovascular disease observed before menopause. However after menopause, estrogen therapy may no longer provide salutary actions because of tissue-specific expression of “coactivator” or “corepressor” proteins, which may interact with the ER resulting in contrasting actions before and after menopause. This is especially possible because ERα and ERβ agonists produce redundant, as well as agonist-specific, proteome profiles.6 Conversely, because Arias-Loza et al6 demonstrated the existence of genomic communication, it will be very interesting to see whether communication also exists between the nongenomic actions elicited by these steroids and, moreover, whether these nongenomic actions modulate the classical actions mediated by steroid receptor activation.
I thank Patricia A. Duggan, MD, for her critical review of this editorial commentary.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Babiker FA, DeWindt LJ, van Eickels M, Thijssen V, Bronsaer RJP, Grohe C, van Bilsen M, Doevendans PA. 17β-Estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation. 2004; 109: 269–276.
Delcayre C, Silvestre JS. Aldosterone and the heart: towards a physiological function? Cardiovasc Res. 1999; 43: 7–12.
Arias-Loza P-A, Hu K, Dienesch C, Mehlich AM, König S, Jazbutyte V, Neyses L, Hegele-Hartung C, Fritzemeier KH, Pelzer T. Both estrogen receptor subtypes, α and β, attenuate cardiovascular remodeling in aldosterone salt-treated rats. Hypertension. 2007; 50: 432–438.
Terry-Lorenzo RT, Elliot E, Weiser DC, Prickett TD, Brautigan DL, Shenolikar S. Neurabins recruit protein phosphatase-1 and inhibitor-2 to the cytoskeleton. J Biol Chem. 2002; 277: 46535–46543.
Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing S-L, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG. Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol. 2002; 22: 4124–4135.