Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats

Abstract

An increasing amount of evidence demonstrates the beneficial role of oxytocin (OT) in the cardiovascular system. Similar actions are attributed to genistein, an isoflavonic phytoestrogen. The treatment with genistein activates the OT system in the aorta of ovariectomized (OVX) Sprague-Dawley (SD) rats. The objective of this study was to determine the effects of low doses of genistein on the OT-induced effects in rat hypertension. The hypothesis tested was that treatment of OVX spontaneously hypertensive rats (SHRs) with genistein improves heart structure and heart work through a mechanism involving the specific OT receptor (OTR). OVX SHRs or SD rats were treated with genistein (in g/g body wt sc, 10 days) in the presence or absence of an OT antagonist (OTA) [d(CH 2)5, Tyr(Me) 2 , Orn 8 ]-vasotocin or a nonspecific estrogen receptor antagonist (ICI-182780). Vehicle-treated OVX rats served as controls. RT-PCR and Western blot analysis demonstrated that left ventricular (LV) OTR, downregulated by ovariectomy, increased in response to genistein. In SHRs or SD rats, this effect was blocked by OTA or ICI-182780 administration. The OTR was mainly localized in microvessels expressing the CD31 marker and colocalized with endothelial nitric oxide synthase. In SHRs, the genistein-stimulated OTR increases were associated with improved fractional shortening, decreased blood pressure (12 mmHg), decreased heart weight-to-body weight ratio, decreased fibrosis, and lowered brain natriuretic peptide in the LV. The prominent finding of the study is the detrimental effect of OTA treatment on the LV of SHRs. OTA treatment of OVX SHRs resulted in a dramatic worsening of ejection fractions and an augmented fibrosis. In conclusion, these results demonstrate that cardiac OTRs are involved in the regulation of cardiac function of OVX SHRs. The decreases of OTRs may contribute to cardiac pathology following menopause. oxytocin receptor; ovariectomy; hypertrophy; genistein THE BIOLOGICAL ACTIVITIES of oxytocin (OT) are associated with reproductive functions, such as uterine contraction, milk ejection, and maternal care. More recently, OT has been found to regulate vascular tone, blood pressure (BP), and kidney function (16). The pathophysiological roles of OT action in the cardiovascular system are beginning to be understood. The heart is a site of OT synthesis and action (15,21,22). In the adult rat heart, OT receptors (OTRs) are mainly expressed in endothelial cells and in cardiomyocytes (21). OTR activation in the heart stimulates cardioprotective reactions, such as negative inotropy and chronotropy, parasympathetic neuromodulation, and the release of atrial natriuretic peptide (ANP) (15) and nitric oxide (NO) (33). OTR-specific signaling induces the differentiation of embryonic stem cells that have been shown to convert to cardiac muscle cells (8,21,35). Recently, we observed that OT increases glucose uptake in cardiomyocytes via the cardioprotective phosphoinositide 3-kinase (PI3K) pathway and potentiates the glucose uptake effect of ...

Preconditioning of Stem Cells by Oxytocin to Improve Their Therapeutic Potential

“…Moreover, OT also increases endothelial cell proliferation and al- ters gene expression for adhesion molecules and MMPs, thus contributing to improved cell motility and growth (25). Furthermore, OT angiogenic and antiapoptotic effects were postulated upon the observation of increased cardiac CD31 ϩ microvessels in ovariectomized rats (29). Our observations in MSC that OT treatment activates the ERK1/2 pathway is also supported by the finding that p38 MAPK and ERK1/2 phosphorylation enhance the proliferative activity of uterine cells (30).…”

The role of oxytocin in cardiovascular regulation

“…Correspondingly, in a rabbit model of myocardial infarction (MI), OT induced cardioprotective gene products such as phosphorylated forms of Akt (i.e., protein kinase B), signal transducer and activator of transcription 3 (STAT3), ERK, matrix metalloproteinase (MMP)-1, and eNOS (35). In the rat heart, an angiogenic and anti-apototic OT effect was indicated by vascular endothelial growth factor (VEGF) and B-cell lymphoma (Bcl)-2 protein upregulation in association with increased CD31 + microvessels (36,37). …”

Protective cardiovascular and renal actions of vitamin D and estrogen

“…Decrements in oxytocin receptor activity are reported to contribute to cardiac pathology by decreases in left ventricular ejection fraction and increases in collagen content, indicative of fibrosis (122). Oxytocin receptors have been demonstrated in cardiomocytes (123) and in the capillary endothelium expressing CD31 colocalized with NO (124).…”