Interaction of the hydrogen sulfide system with the oxytocin system in the injured mouse heart

Abstract

Background: Both the hydrogen sulfide/cystathionine-γ-lyase (H₂S/CSE) and oxytocin/oxytocin receptor (OT/OTR) systems have been reported to be cardioprotective. H₂S can stimulate OT release, thereby affecting blood volume and pressure regulation. Systemic hyper-inflammation after blunt chest trauma is enhanced in cigarette smoke (CS)-exposed CSE^-/- mice compared to wildtype (WT). CS increases myometrial OTR expression, but to this point, no data are available on the effects CS exposure on the cardiac OT/OTR system. Since a contusion of the thorax (Txt) can cause myocardial injury, the aim of this post hoc study was to investigate the effects of CSE^-/- and exogenous administration of GYY4137 (a slow release H₂S releasing compound) on OTR expression in the heart, after acute on chronic disease, of CS exposed mice undergoing Txt.

Methods: This study is a post hoc analysis of material obtained in wild type (WT) homozygous CSE^-/- mice after 2-3 weeks of CS exposure and subsequent anesthesia, blast wave-induced TxT, and surgical instrumentation for mechanical ventilation (MV) and hemodynamic monitoring. CSE^-/- animals received a 50 μg/g GYY4137-bolus after TxT. After 4h of MV, animals were exsanguinated and organs were harvested. The heart was cut transversally, formalin-fixed, and paraffin-embedded. Immunohistochemistry for OTR, arginine-vasopressin-receptor (AVPR), and vascular endothelial growth factor (VEGF) was performed with naïve animals as native controls.

Results: CSE^-/- was associated with hypertension and lower blood glucose levels, partially and significantly restored by GYY4137 treatment, respectively. Myocardial OTR expression was reduced upon injury, and this was aggravated in CSE^-/-. Exogenous H₂S administration restored myocardial protein expression to WT levels.

Conclusions: This study suggests that cardiac CSE regulates cardiac OTR expression, and this effect might play a role in the regulation of cardiovascular function.

Keywords: Arginine-vasopressin receptor; Blood glucose; Cardiovascular system; Cystathionine-γ-lyase; GYY4137; Vascular endothelial growth factor.

Fig. 1

Immunohistochemistry. Exemplary pictures (top left native, top right WT CS Txt, bottom left CSE^−/− CS Txt, bottom right CSE^−/− CS Txt GYY4137, respectively) of left-ventricular myocardium (ventricular lumen to the right) and densitometric analysis for OTR expression (a, b), AVPR expression (c, d), and VEGF expression (e, f). Data given as box plots (median, interquartile range, minimum and maximum). Boxplots represent N = 4 (native) and N = 8 (experimental groups). Open arrow cardiomyocyte, bold arrow cardiac microvasculature