Maternal Separation Induces Long-Term Alterations in the Cardiac Oxytocin Receptor and Cystathionine γ-Lyase Expression in Mice.

Daniela C Wigger,Nicole Gröger,Jörg Bock,Oscar Mccook,Christiane Waller,Alexandra Lesse,Tamara Merz,Sabrina Krause,Katharina Braun,Peter Radermacher,Harald Gündel

doi:10.1155/2020/4309605

Abstract

We recently showed that blunt chest trauma reduced the expression of the myocardial oxytocin receptor (Oxtr), which was further aggravated by genetic deletion of the H2S-producing enzyme cystathionine γ-lyase (CSE). Exogenous H2S supplementation restored myocardial Oxtr expression under these conditions. Early life stress (ELS) is a risk factor for cardiovascular disease by affecting vascular and heart structures. Therefore, we tested the hypotheses that (i) ELS affects cardiac Oxtr and CSE expressions and (ii) Oxtr and CSE expression patterns depend on the duration of stress exposure. Thus, two stress paradigms were compared: long- and short-term separation stress (LTSS and STSS, respectively). Cardiac Oxtr expression was differentially affected by the two stress paradigms with a significant reduction after LTSS and a significant increase after STSS. CSE expression, which was significantly reduced in Oxtr−/− knockout hearts, was downregulated and directly related to Oxtr expression in LTSS hearts (r = 0.657, p = 0.012). In contrast, CSE expression was not related to Oxtr upregulation in STSS. Plasma Oxt levels were not affected by either ELS paradigm. The coincidence of LTSS-induced reduction of cardiac Oxtr and reduced CSE expression may suggest a novel pathophysiological link between early life adversities and increased risk for the development of cardiovascular disorders in adulthood.

Highlights

Maternal separation (MS) is a robust and widely used animal model for inducing early life stress (ELS), a paradigm that is applied using different protocols, especially regarding the duration and time point of stress exposure [1, 2]
We have recently shown that the slow-releasing H2S donor GYY4137 restored the myocardial oxytocin receptor (Oxtr) expression in mice lacking the H2S-generating enzyme cystathionine γ-lyase (CSE) that had undergone cigarette smoke exposure to induce chronic obstructive pulmonary disease (COPD) prior to blunt chest trauma [32]
The present study tested the hypotheses (i) whether two different ELS paradigms, i.e., “chronic” long-term separation stress (LTSS) and “mild” STSS, affect the Oxtr and CSE expression in adult cardiac tissue, (ii) if this effect is “dose”-dependent, and (iii) whether ELSinduced changes of Oxtr and CSE expression are correlated. In line with these hypotheses, we found that early postnatalinduced changes of adult cardiac Oxtr expression were critically dependent on the “dose” of ELS exposure, while LTSS resulted in reduced Oxtr expression in adult cardiac tissue compared to controls; the opposite was found after STSS, i.e., upregulation of Oxtr expression

Summary

Introduction

Maternal separation (MS) is a robust and widely used animal model for inducing early life stress (ELS), a paradigm that is applied using different protocols, especially regarding the duration and time point of stress exposure [1, 2]. Since ELS, such as childhood maltreatment, may provide a critical programing factor for the development of coronary artery disease (CAD), diabetes [17], and hypertension [18] at later life periods, it is tempting to speculate that these effects might at least in part be mediated by ELS-induced changes of Oxt function. This hypothesis is supported by studies in animal models showing that MS results in cardiac changes including cardiomyocyte hypertrophy as well as cardiac fibrosis [19]. These alterations are induced by superoxide production and endothelial dysfunction [24], inflammation [25], and sensitizing of the renal and sympathetic systems [26]

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