The Role of Oxytocin in Cardiovascular Protection.

The beneficial effects of oxytocin on infarct size and functional recovery of the ischemic reperfused heart are well documented. The mechanisms for this cardioprotection are not well defined. Evidence indicates that oxytocin treatment improves cardiac work, reduces apoptosis and inflammation, and increases scar vascularization.

Dissociation of natriuresis and diuresis by oxytocin molecular forms in rats.

In the rat, oxytocin (OT) produces dose-dependent diuretic and natriuretic responses. Post-translational enzymatic conversion of the OT biosynthetic precursor forms both mature and C-terminally extended peptides. The plasma concentrations of these C-terminally extended peptides (OT-G; OT-GK and OT-GKR) are elevated in newborns and pregnant rats.

Anti-inflammatory and angiogenic effects of exercise training in cardiac muscle of diabetic mice.

Improved glycemic control and cardiovascular function are major benefits of regular exercise training (ET) in type 2 diabetes. Recent work has demonstrated that ET improves cardiac and vascular functions independent of obesity, inflammation, and glucose control in the diabetic db/db mouse. In this study, we determined whether ET can overcome the effects of elevated inflammatory cytokines and hyperglycemia on markers of cardiac angiogenesis and inflammation in the diabetic mouse.

The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse.

Background: Regular exercise training (ET) and caloric restriction (CR) are the frontline strategies in the treatment of type 2 diabetes mellitus with the aim at reducing cardiometabolic risk. ET and CR improve body weight and glycemic control, and experimental studies indicate that these paradigms afford cardioprotection. In this study, the effects of combined ET and CR on the cardioprotective oxytocin (OT)-natriuretic peptide (NP) system were determined in the db/db mouse, a model of type 2 diabetes associated with insulin resistance, hyperglycemia, and obesity.

Prorenin/renin receptor blockade promotes a healthy fat distribution in obese mice.

Objective: Administration of the handle region peptide (HRP), a (pro)renin receptor blocker, decreases body weight gain and visceral adipose tissue (VAT) in high-fat/high-carbohydrate (HF/HC) diet-fed mice. The objective of this study was to elucidate potential mechanisms implicated in these observations.

Methods: Mice were given a normal or a HF/HC diet along with saline or HRP for 10 weeks.

Oxytocin and cardioprotection in diabetes and obesity.

Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects.

Oxytocin decreases diurnal and nocturnal arterial blood pressure in the conscious unrestrained spontaneously hypertensive rat.

In this study, we assessed the effects of oxytocin (OT) on mean arterial blood pressure (MAP), heart rate (HR), and locomotor activity (LA) in male spontaneous hypertensive rats (SHR) and Sprague-Dawley (SDR) controls using telemetry. OT was given by intravenous injections of 0.1, 0.

Molecular mechanisms underlying oxytocin-induced cardiomyocyte protection from simulated ischemia-reperfusion.

Oxytocin (OT) stimulates cardioprotection. Here we investigated heart-derived H9c2 cells in simulated ischemia-reperfusion (I-R) experiments in order to examine the mechanism of OT protection. I-R was induced in an anoxic chamber for 2 hours and followed by 2 h of reperfusion.

Oxytocin treatment prevents the cardiomyopathy observed in obese diabetic male db/db mice.

Oxytocin (OT) is involved in the regulation of energy metabolism and in the activation of cardioprotective mechanisms. We evaluated whether chronic treatment with OT could prevent the metabolic and cardiac abnormalities associated with diabetes and obesity using the db/db mice model. Four-week-old male db/db mice and their lean nondiabetic littermates (db/+) serving as controls were treated with OT (125 ng/kg · h) or saline vehicle for a period of 12 weeks.

Impact of the prorenin/renin receptor on the development of obesity and associated cardiometabolic risk factors.

Objective: Obesity is a worldwide epidemic and current treatments have limited success thus, novel therapies are warranted. Our objective was to determine whether the prorenin/renin receptor [(P)RR] is implicated in obesity.

Methods: Mice received a normal or high-fat/high-carbohydrate diet with the handle region peptide (HRP), a (P)RR blocker, or saline for 10 weeks.

All-trans retinoic acid stimulates gene expression of the cardioprotective natriuretic peptide system and prevents fibrosis and apoptosis in cardiomyocytes of obese ob/ob mice.

In hypertensive rodents, retinoic acid (RA) prevents adverse cardiac remodelling and improves myocardial infarction outcome, but its role in obesity-related changes of cardiac tissue are unclear. We hypothesized that all-trans RA (ATRA) treatment will improve the cardioprotective oxytocin-natriuretic peptides (OT-NP) system, preventing apoptosis and collagen accumulation in hearts of ob/ob mice, a mouse model of obesity and insulin resistance. Female 9-week-old B6.

Anti-hypertrophic effects of oxytocin in rat ventricular myocytes.

Background: Oxytocin (OT) and functional OT receptor (OTR) are expressed in the heart and are involved in blood pressure regulation and cardioprotection. Cardiac OTR signaling is associated with atrial natriuretic peptide (ANP) and nitric oxide (NO) release. During the synthesis of OT, its precursor, termed OT-Gly-Lys-Arg (OT-GKR), is accumulated in the developing rat heart.

Treatment with brain natriuretic peptide prevents the development of cardiac dysfunction in obese diabetic db/db mice.

Aims/hypothesis: Obesity and diabetes increase the risk of developing cardiovascular diseases and heart failure. These metabolic disorders are generally reflected by natriuretic peptide system deficiency. Since brain natriuretic peptide (BNP) is known to influence metabolism and cardioprotection, we investigated the effect of chronic exogenous BNP treatment on adverse myocardial consequences related to obesity and diabetes.

Oxytocin-Gly-Lys-Arg stimulates cardiomyogenesis by targeting cardiac side population cells.

The functional oxytocin (OT) system is expressed in the human and rodent hearts. OT stimulates differentiation of cardiac stem cells into contracting cardiomyocytes (CM). In this study, we investigated OT receptors (OTR) expressed in the cells of cardiac side population (SP) and the abilities of these cells to differentiate into CM in response to the treatment with OT-Gly-Lys-Arg (OT-GKR), a dominant and biologically active form of OT, in the fetal rodent heart.

Unexpected effects of voluntary exercise training on natriuretic peptide and receptor mRNA expression in the ob/ob mouse heart.

Regular exercise is generally recommended for the treatment of obesity and type 2 diabetes. Exercise reduces body weight, improves glycemic control and cardiovascular (CV) function. This study was designed to determine the impact of voluntary wheel running on the cardiac oxytocin (OT)-natriuretic peptide (NP) system and plasma CV risk factors in the ob/ob mouse, a model of insulin resistance coupled with severe obesity.

Novel role of the renin-angiotensin system in preeclampsia superimposed on chronic hypertension and the effects of exercise in a mouse model.

Gestational hypertensive disorders, such as preeclampsia, affect 6% to 8% of all pregnancies in North America, and they are the leading cause of maternal mortality in industrialized countries, accounting for 16% of deaths. Women with hypertension have an increased risk (15% to 25%) of developing preeclampsia. Our aim was to investigate the mechanisms implicated in preeclampsia superimposed on chronic hypertension and in the protective effects of exercise in a mouse model.

Impact of exercise training on preeclampsia: potential preventive mechanisms.

Preeclampsia is characterized by hypertension and de novo proteinuria after 20 weeks of pregnancy. It is the leading cause of perinatal morbidity and mortality in the developed world, and to date, the only means of treating the disease is by inducing delivery. Many studies have shown the benefits of exercise training on normal pregnancy.

Preconditioning of stem cells by oxytocin to improve their therapeutic potential.

Principal limitation of cell therapy is cell loss after transplantation because of the interplay between ischemia, inflammation, and apoptosis. We investigated the mechanism of preconditioning of mesenchymal stem cells (MSCs) with oxytocin (OT), which has been proposed as a novel strategy for enhancing therapeutic potential of these cells in ischemic heart. In this study, we demonstrate that rat MSCs express binding sites for OT receptor and OT receptor transcript and protein as detected by RT-PCR and immunofluorescence, respectively.

Expression of cardiac GATA4 and downstream genes after exercise training in the db/db mouse.

GATA4 is a transcriptional factor expressed in heart that regulates the synthesis of structural and cardioprotective genes. We have demonstrated that low GATA4 expression in the db/db mouse heart is associated with reduced expression of key downstream genes, including oxytocin (OT) natriuretic peptide (A-, B-type), nitric oxide synthase (eNOS), and myosin heavy chain (α-MHC). In this study, the effect of exercise on GATA4 expression and related genes was determined in the db/db mouse, a model that represents human type 2 diabetes.

Downregulation in GATA4 and Downstream Structural and Contractile Genes in the db/db Mouse Heart.

Reduced expression of GATA4, a transcriptional factor for structural and cardioprotective genes, has been proposed as a factor contributing to the development of cardiomyopathy. We investigated whether the reduction of cardiac GATA4 expression reported in diabetes alters the expression of downstream genes, namely, atrial natriuretic peptide (ANP), B-type natriuretic, peptide (BNP), and α- and β-myosin heavy chain (MHC). db/db mice, a model of type 2 diabetes, with lean littermates serving as controls, were studied.

Oxytocin in the heart regeneration.

We have demonstrated that entire oxytocin (OT) system is synthesized in the rat and human heart and this hormone is implicated in several cardiac functions including stem cells differentiation into cardiomyocytes. These observations led us to the invention of OT as an inducer of cardiomyogenesis (US20060205636A1). We also proposed the use of OT, its functional derivatives, and/or physiological precursors as well as nucleic acids capable of encoding OT as cell-differentiating and useful agents for treating or preventing diseases, such as heart diseases associated with loss of cardiomyocytes.

The effects of exercise training on γ-butyrobetaine hydroxylase and novel organic cation transporter-2 gene expression in the rat.

The concentration of carnitine in plasma is generally increased with exercise training, suggesting that either carnitine biosynthesis is stimulated or renal reabsorption of carnitine is enhanced, or both. Carnitine, an essential cofactor in the oxidation of fatty acids, is released into the plasma following hydroxylation by γ-butyrobetaine hydroxylase (BBH), the final enzyme in the biosynthetic pathway found primarily in the liver. The organic cation transporter (OCTN2), the carnitine transporter found in kidney, is important in the distribution of carnitine by facilitating its renal reabsorption from urine.

Effects of exercise training on molecular markers of lipogenesis and lipid partitioning in fructose-induced liver fat accumulation.

The present study was designed to investigate the impact of exercise training on lipogenic gene expression in liver and lipid partitioning following the ingestion of a high fructose load. Female rats were exercise-trained for 8 wk or kept sedentary before being submitted to a fasting/refeeding protocol. Rats were further subdivided as follow: rats were fasted for 24 h, refed a standard diet for 24 h, starved for another 24 h, and refed with a standard or a high-fructose diet 24 h before sacrifice.

Changes in cardiac structure in hypertension produced by placental ischemia in pregnant rats: effect of tumor necrosis factor blockade.

Objectives: Chronic reduction of uteroplacental perfusion pressure (RUPP) in pregnant rats leads to placental ischemia, maternal endothelial cell dysfunction, hypertension and elevated levels of tumor necrosis factor-alpha (TNF-α). In this study we investigated the hypothesis that placental ischemia in pregnant rat, a model of preeclampsia, stimulates cardiac hypertrophy and fibrosis via a TNF-α-dependent mechanism.

Methods: Normal pregnant Sprague-Dawley rats and RUPP rats were evaluated on day 19 of gestation.