Oxytocin-Gly-Lys-Arg: A Novel Cardiomyogenic Peptide

Background: Oxytocin (OT), synthesized in the heart, has the ability to heal injured hearts and to promote cardiomyogenesis from stem cells. Recently, we reported that the OT-GKR molecule, a processing intermediate of OT, potently increased the spontaneous formation of cardiomyocytes (CM) in embryonic stem D3 cells and augmented glucose uptake in newborn rat CM above the level stimulated by OT. In the present experiments, we investigated whether OT-GKR exists in fetal and newborn rodent hearts, interacts with the OT receptors (OTR) and primes the generation of contracting cells expressing CM markers in P19 cells, a model for the study of early heart differentiation. Methodology/Principal Findings: High performance liquid chromatography of newborn rat heart extracts indicated that OT-GKR was a dominant form of OT. Immunocytochemistry of mouse embryos (embryonic day 15) showed cardiac OT-GKR accumulation and OTR expression. Computerized molecular modeling revealed OT-GKR docking to active OTR sites and to V1a receptor of vasopressin. In embryonic P19 cells, OT-GKR induced contracting cell colonies and ventricular CM markers more potently than OT, an effect being suppressed by OT antagonists and OTR-specific small interfering (si) RNA. The V1a receptor antagonist and specific si-RNA also significantly reduced OT-GKR-stimulated P19 contracting cells. In comparison to OT, OT-GKR induced in P19 cells less a-actinin, myogenin and MyoD mRNA, skeletal muscle markers. Conclusions/Significance: These results raise the possibility that C-terminally extended OT molecules stimulate C

Atrial natriuretic factor during atrial fibrillation and supraventricular tachycardia

Plasma immunoreactive atrial natriuretic factor was measured in 10 patients with chronic atrial fibrillation before and after cardioversion to sinus rhythm, and in 14 patients during electrophysiologic evaluation of paroxysmal supraventricular tachycardia. The mean plasma concentration of atrial natriuretic factor in atrial fibrillation was 138 ± 48 pg/ml and decreased to 116 ± 45 pg/ml 1 hour after cardioversion to sinus rhythm (p < 0.005). The mean plasma concentration of atrial natriuretic factor increased from 117 ± 53 pg/ml in sinus rhythm to 251 ± 137 pg/ml during laboratory-induced supraventricular tachycardia (p < 0.005). Right atrial pressures were recorded in 12 patients; the baseline atrial pressure was 4.3 ± 1.9 mm Hg and increased to 7.4 ± 3.6 mm Hg during supraventricular tachycardia (p < 0.005). A modest but significant linear relation was noted between the changes in plasma atrial natriuretic factor and right atrial pressure measurements during induced supraventricular tachycardia (r = 0.60, p < 0.05).In conclusion, changes in atrial rhythm and pressure may be an important factor modulating the release of atrial natriuretic factor in the circulation and raised levels of this hormone may be a contributing factor for the polyuria and the hypotension associated with paroxysmal supraventricular tachyarrhythmias

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. Fructose refeeding was associated with an increase in hepatic lipid content, endocannabinoid receptor 1, sterol regulatory element-binding protein1c, and stearoyl-CoA desaturase1 gene expression in both Sed and TR rats. However, desaturation indexes measured in liver (C16 : 1/C16 : 0 and C18 : 1/C18 : 0) and plasma (C18 : 1/C18 : 0) were higher (P < 0.01) in TR than in Sed rats following fructose refeeding. It is concluded that exercise training does not significantly affect fat accumulation and the molecular expression of genes involved in lipogenesis after fasting and fructose refeeding but does modify the partitioning of lipids so as to provide more unsaturated fatty acids in liver without affecting liver fat content

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. db/db mice exhibited obesity, hyperglycemia, and reduced protein expression of cardiac GLUT4 and IRAP (insulin-regulated aminopeptidase), the structural protein cosecreted with GLUT4. Hearts from db/db mice had reduced protein expression of GATA4 (~35%) with accompanying reductions in mRNA expression of ANP (~40%), BNP (~85%), and α-MHC mRNA (~50%) whereas expression of β-MHC mRNA was increased by ~60%. Low GATA4 was not explained by an increased ligase or atrogin1 expression. CHIP protein content was modestly downregulated (27%) in db/db mice whereas mRNA and protein expression of the CHIP cochaperone HSP70 was significantly decreased in db/db hearts. Our results indicate that low GATA4 in db/db mouse heart is accompanied by reduced expression of GATA4-regulated cardioprotective and structural genes, which may explain the development of cardiomyopathy in diabetes

Oxytocin: Old Hormone, New Drug

Oxytocin (OT), traditionally associated with reproductive functions, was revisited recently, and several new functions in cardiovascular regulation were discovered. These functions include stimulation of the cardioprotective mediators nitric oxide (NO) and atrial natriuretic peptide. OT’s cardiovascular outcomes comprise: (i) natriuresis, (ii) blood pressure reduction, (iii) negative inotropic and chronotropic effects, (iv) parasympathetic neuromodulation, (v) NO pathway involvement in vasodilatation and endothelial cell growth, (vi) anti-inflammatory and (vii) antioxidant activities as well as (viii) metabolic effects. In addition, we have reported abundant OT in the early developing heart with its capacity to generate cardiomyocytes (CMs) from mouse embryonic stem cells and stem cells residing in the heart. OT increases glucose uptake by cultured CMs, in normal, hypoxic and even in insulin resistance conditions. In experimentally-induced myocardial infarction in rats, continuous in vivo OT delivery improves the cardiac healing process and cardiac work, diminishes inflammation, and stimulates angiogenesis. Therefore, in pathological situations, OT plays an anti-inflammatory and cardioprotective role, enhancing vascular and metabolic functions, with potential therapeutic application(s)

Oxytocin: Old Hormone, New Drug

Oxytocin (OT), traditionally associated with reproductive functions, was revisited recently, and several new functions in cardiovascular regulation were discovered. These functions include stimulation of the cardioprotective mediators nitric oxide (NO) and atrial natriuretic peptide. OT’s cardiovascular outcomes comprise: (i) natriuresis, (ii) blood pressure reduction, (iii) negative inotropic and chronotropic effects, (iv) parasympathetic neuromodulation, (v) NO pathway involvement in vasodilatation and endothelial cell growth, (vi) anti-inflammatory and (vii) antioxidant activities as well as (viii) metabolic effects. In addition, we have reported abundant OT in the early developing heart with its capacity to generate cardiomyocytes (CMs) from mouse embryonic stem cells and stem cells residing in the heart. OT increases glucose uptake by cultured CMs, in normal, hypoxic and even in insulin resistance conditions. In experimentally-induced myocardial infarction in rats, continuous in vivo OT delivery improves the cardiac healing process and cardiac work, diminishes inflammation, and stimulates angiogenesis. Therefore, in pathological situations, OT plays an anti-inflammatory and cardioprotective role, enhancing vascular and metabolic functions, with potential therapeutic application(s)

RAPID COMMUNICATIONS REDUCTION OF BLOOD PRESSURE AND INCREASED D IURESIS AND NATRIURESIS DURING CHRONIC INFUSION OF ATRIAL NATRIURETIC FACTOR (ANF Arg 101-Tyr 126) I N CONSCIOUS ONE-KIDNEY, ONE-CLIP HYPERTENSIVE RATS

Abstract. Conscious one-kidney , one-cl ip hypertensive rats and their normotensive controls were infused during 7 days with synthetic ANF (Arg 101-Tyr 126) at 100 ng/hr/rat (35 pmol/hr/rat) by means of osmotic minipumps. The basal blood pressure of 193 + 6 mmHg gradually declined to 145 + 6 mmHg at day 4 after the infusion was started. No changes in blood pressure were observed in ANF-infused normotensive rats. A sign if icantly higher diuresis and natriuresis was observed in ANF-infused hypertensive rats when compared to the non-treated hypertensive group. No such changes were observed in ANF-treated normotensive animals. No differences in PRA were seen in any group. Atrial immunoreactive ANF was significantly lower in one-kidney, one-cl ip rats than in the normotensive animals, but whether this is the reflection of an increased release in the circulation remains to be elucidated. It is suggested that the hypotens ive response of one-kidney , one-c 1 ip animals to ANF may be secondary to a dual mechanism, vasodilatation and V O~ ume depletion. @ 1985 s o c i e t y f o r Experimental Biology and Medicine