Relaxin binding in the rat heart atrium.

Abstract

Relaxin is a member of the insulin family of polypeptides that is best known as a reproductive hormone. In an effort to elucidate the mechanism of action of relaxin we previously localized the specific binding sites of a 32P-labeled relaxin in the rat uterus and brain. These studies suggested that, in addition to its classical role in pregnancy, relaxin might have other physiological functions. In the present paper we describe the specific and high-afminity binding of relaxin to the cardiac atrium of both male and female rats. The relaxin binding could not be displaced by peptides belonging to the same family [insulin, insulin-like growth factor I (IGF-I)] or by peptides that were identified in the atrium or were known to have cardiovascular functions (atrial natriuretic peptide, angiotensin II). The dissociation constant for relaxin in the atrium was estimated to be 1.4 nM, which was similar to that found in the uterus (1.3 nM) and the brain (1.4 nM). In view of the close association of relaxin with reproduction, an experiment was also performed to compare the relaxin binding in the uterus and heart after gonadectomy and sex steroid treatment. It was found that the relaxin binding in the rat uterus was diminished by 53% overall following ovariectomy but was restored to 90% of normal levels when treated with estrogen (but not with testosterone). In contrast, the relaxin binding in the rat heart was not affected by castration or sex steroid treatment. We conclude that specific and high-affinity relaxin receptors exist in the atrium of both the male and female rat heart and that these are regulated differently than the relaxin receptors in the uterus.Relaxin is structurally related to insulin and insulin-like growth factors and is best known as a pregnancy-associated hormone (1, 2). In addition to its classical actions on cervical ripening, uterine contraction, and pubic symphysis elongation (1, 2), relaxin has been suggested to participate in the regulation of blood pressure (3-8) and neuropeptide release, notably oxytocin and vasopressin (9-13). However, the results from these studies were conflicting, and the site of action of relaxin was undetermined. Biochemical support for these hypotheses was provided when it was shown that, in addition to the uterus and cervix (14), relaxin bound with specificity and high affinity (Kd 1 nM) to several sites in the male and female rat brain (15). Some of these sites, in particular two of the circumventricular organs (subfornical organ and organum vasculosum of the lamina terminalis) and the magnocellular hypothalamic nuclei (paraventricular and supraoptic nucleus) are known to be involved in the control of blood pressure, fluid balance, and the release of neuropeptides. To further investigate the mechanism of action of relaxin, we continued the search for relaxin target tissues and were surprised to observe the specific and high-affinity binding of relaxin to the atrium of the rat heart. We also show that the atrial binding is regulated differently than the uterus. ...

Evidence for expression of relaxin hormone-receptor system in the boar testis

“…Oestrogen is considered to be one of the candidate factors regulating RLN receptor, but the effect is different between tissues and/or genders. Administration of oestradiol-17b into female rats increases the RLN-binding sites in the uterus but has no effect in atria and cerebral cortex, whereas the identical treatment in male rats reduces the RLN-binding sites in these tissues (Osheroff et al 1992, Tan et al 1999. More recent studies in neonatal porcine uterus and cervix have shown an increase in PXFP1 expression by oestradiol-17b administration (Yan et al 2008a).…”

Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

“…Relaxin has been reported to enhance cAMP formation in human endometrial (29) and anterior pituitary cells (30), to inhibit Ca 2 ϩ influx in myometrial cells (31) and mast cells (32), and to induce protein kinase C translocation from cytosol to membranes in endometrial cells (33). Additionally, binding of relaxin to certain cell types is estrogen-dependent while binding to others is not (34), and certain phenotypic alterations are dependent on the presence of both relaxin and estrogen while others are not (17). Cells derived from reproductive tissues, such as the cervix and uterus, tend to depend on estrogen pre-exposure in vivo, while binding to (34) and phenotypic effects on cells from nonreproductive tissues, such as skin or lungs (Unemori, unpublished observations), tend to be estrogen-independent.…”

“…Additionally, binding of relaxin to certain cell types is estrogen-dependent while binding to others is not (34), and certain phenotypic alterations are dependent on the presence of both relaxin and estrogen while others are not (17). Cells derived from reproductive tissues, such as the cervix and uterus, tend to depend on estrogen pre-exposure in vivo, while binding to (34) and phenotypic effects on cells from nonreproductive tissues, such as skin or lungs (Unemori, unpublished observations), tend to be estrogen-independent. In summary, we have found that relaxin can induce an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and can inhibit lung fibrosis in a murine bleomycin model.…”

Relaxin remodels fibrotic healing following myocardial infarction

“…This is apparently due to a much lower density of relaxin receptors in the atria of humans than that in rodents. 41 Thus, relaxin's tachycardiac effects should not be a clinical concern.…”