The Role of Oxytocin in Cardiovascular Protection

Abstract

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. Oxytocin-mediated cytoprotection involves the production of cGMP stimulated by local release of atrial natriuretic peptide and synthesis of nitric oxide. Treatment with oxytocin reduces the expression of proinflammatory cytokines and reduces immune cell infiltration. Oxytocin also stimulates differentiation stem cells to cardiomyocyte lineages as well as generation of endothelial and smooth muscle cells, promoting angiogenesis. The beneficial actions of oxytocin may include the increase in glucose uptake by cardiomyocytes, reduction in cardiomyocyte hypertrophy, decrease in oxidative stress, and mitochondrial protection of several cell types. In cardiac and cellular models of ischemia and reperfusion, acute administration of oxytocin at the onset of reperfusion enhances cardiomyocyte viability and function by activating Pi3K and Akt phosphorylation and downstream cellular signaling. Reperfusion injury salvage kinase and signal transducer and activator of transcription proteins cardioprotective pathways are involved. Oxytocin is cardioprotective by reducing the inflammatory response and improving cardiovascular and metabolic function. Because of its pleiotropic nature, this peptide demonstrates a clear potential for the treatment of cardiovascular pathologies. In this review, we discuss the possible cellular mechanisms of action of oxytocin involved in cardioprotection.

Keywords: atrial natriuretic peptide; cardiomyocyte; heart; oxytocin; oxytocin—therapeutic use.

FIGURE 1

Schematic representation of the centrally mediated actions of oxytocin treatment on blood pressure regulation. Intracerebrovascular injections of OT increase α-2 adrenoreceptor responsiveness in the LC and NTS. Within the NTS, impulses reach the medullary cardiovascular center of the medulla oblongata where the baroreceptor afferents are activated to variations in arterial pressure. When arterial pressure is elevated or in with injections of OT, inhibitory neurons in the CVLM that extend to the RVLM, which regulates sympathetic nervous tone from the spinal cord to peripheral organs, are activated. Activation of this pathway suppresses peripheral sympathetic outflow to the heart and peripheral resistance vessels, leading to bradycardia and vasodilation of these vessels, respectively, and a decrease in arterial pressure. In addition, intracerebrovascular administered OT activates the oxytocinergic neurons and stimulates the synthesis and release of OT from the posterior pituitary. Plasma OT binds to the OTRs in cardiac tissue to induce a bradycardia and the release of ANP. OT also binds to the OTRs present in the vasculature, causing vasodilation. ANP, atrial natriuretic peptide; CVLM, caudal ventrolateral medulla; DMN, dorsal motor nucleus of the vagus nerve; LC, locus coeruleus; NTS, nucleus tractus solitarius; OT, oxytocin; OTR, oxytocin receptor; PVN, paraventricular nuclei; RVLM, rostral ventrolateral medulla; SON, supraoptic nuclei.

FIGURE 2

Schematic diagram of the role of OT in the regulation arterial blood pressure. Activation of the baroreceptor (renal, aortic, and carotid) reflex to an increase in blood volume expansion or hypertension and subsequent integration of the afferent signals within the NTS activates oxytocinergic neurons. This induces the synthesis of OT from the PVN and SON of the hypothalamus and release into the plasma. In plasma, OT can bind to OTRs found in the heart, kidney, and vasculature. The heart is also a source of OT where it can also bind to its receptors. Activation of the OTR in the heart induces bradycardia and a decrease in inotropy as well as the release of ANP and NO. Release of cardiac ANP induces vasodilation of peripheral arterioles after binding to the NPR-A. The effect of OT on peripheral vasodilation is a NO-dependent vasodilation effect. ANP also binds to NPR-A receptors in the renal vascular. Physiological concentrations of OT and ANP induce arteriolar dilation, leading to diuresis, natriuresis, kaliuresis, and a decrease in plasma volume. The net effect is a decrease in arterial pressure. High levels of OT in either plasma or centrally produced from the oxytocinergic system are known to suppress the hypothalamus–pituitary–adrenal axis. This decreases CRF release from the hypothalamus and decreases production of ACTH and cortisol. ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; AP, anterior pituitary; CRF, corticotropin-releasing hormone; NO, nitric oxide; NPR-A, natriuretic peptide receptor, type A; NTS, nucleus tractus solitarius; OT, oxytocin; OTn, oxytocinergic neurons; OTR, oxytocin receptor; PP, posterior pituitary; PVN, paraventricular nuclei; SON, supraoptic nuclei.

FIGURE 3

Schematic diagram of hypothetical OT signaling pathways targeting the nucleus and mitochondria in the cardiac cells. Multiple mechanisms stimulated by the OTR can contribute to the beneficial effects in cardiac cells. OTR activates GTP-binding proteins of the G alpha q/11 class, which stimulate phospholipase C activity, IP3 generation, and release of calcium from intracellular stores. Changes in calcium stimulate ANP release from cardiac atrial deposits and subsequent activation of particulate guanylyl cyclase and cGMP production. Activation of PI3K signaling pathway is also involved in cardioprotection. This results in phosphorylation and activation of AKT and NOS activation and NO production. NO stimulates soluble guanylyl cyclase also producing cGMP. cGMP has been linked to activate the mitochondrial mKATP channel. Activation of the PI3K/ERK1/2 pathways also leads to phosphorylation and inactivation of GSK. Inhibition of GSK has also been reported to inhibit the mPTP. Activation of the mKATP channels stimulates the inhibitory phosphorylation of GSK-3b and inhibits ROS production. NO also induces protein S-nitrosylation (SNO). SNO of the L-type calcium channel reduces calcium entry and the amount of calcium that enters the mitochondria. This inhibits the effect of calcium on the activation of the mPTP. SNO effects on complex I results in lowered production of ROS. In effect, these beneficial signaling pathways cause reduction in calcium and ROS triggers for mPTP. In addition, cGMP stimulates cGKIα, which interacts with mitochondrial large conductance calcium-activated potassium channel, stimulating potassium influx in mitochondria. This effect may lead closure of the mPTP and cardioprotection. ANP, atrial natriuretic peptide; NO, nitric oxide; OT, oxytocin; OTR, oxytocin receptor; ROS, reactive oxygen species. AC, adenylate cyclase; AMPK, AMP-activated protein kinase; AKT, protein kinase B; ANP, atrial natriuretic peptide; CaM, calmodulin; CaMKK, Ca²⁺ calmodulin-dependent protein kinase kinase; CaMK, Ca²⁺/calmodulin-dependent protein kinase; cGKI, cGMP-dependent protein kinase type Iα; cGMP, cyclic guanosine monophosphate (DAG) diacyl glycerol; (EC) endothelial cells; eEF2, elongation factor 2; ERK, extracellular signal-regulated kinases; GATA4, GATA binding protein 4; GSK3β, glycogen synthase kinase 3 beta; IP3, inositol 1,4,5-trisphosphate; JAK, Janus kinase; mBK, mitochondrial BKCa channel; MEK5, mitogen-activated protein kinase kinase 5; mKATP, mitochondrial K_ATP channels; MnSOD, manganese superoxide dismutase; NFAT, nuclear factor of activated T-cells; NOS, NO synthase; NPR-A, natriuretic peptide receptor A; pGC, particulate guanylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; PI3K, phosphatidyl-3 kinase; mPTP, mitochondrial permeability transition pore; SNO, S-nitrosothiol; STAT3, signal transducer and activator of transcription 3; TKs, receptor tyrosine kinases.