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

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.

The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System

“…OT plasma levels were positively related to improved cardiovascular and sympathetic responses to stress [ 112 ]. In mice, early life stress led to a significant long-term reduction of both cardiac CSE and OTR expression to the same degree [ 113 ]. Moreover, OTR knock out (OTRko) mice presented with reduced cardiac CSE expression, providing another confirmation of the link between the OT and H 2 S systems [ 113 ].…”

“…In mice, early life stress led to a significant long-term reduction of both cardiac CSE and OTR expression to the same degree [ 113 ]. Moreover, OTR knock out (OTRko) mice presented with reduced cardiac CSE expression, providing another confirmation of the link between the OT and H 2 S systems [ 113 ]. Interestingly, OTR expression was dependent on the “stress-dose”, inasmuch as “long-term” stressed (LTSS) mice had decreased OTR protein expression, whereas the “short-term” stressed (STSS) group displayed increased OTR expression [ 113 ].…”

“…Interestingly, OTR expression was dependent on the “stress-dose”, inasmuch as “long-term” stressed (LTSS) mice had decreased OTR protein expression, whereas the “short-term” stressed (STSS) group displayed increased OTR expression [ 113 ]. This led the authors to conclude that the LTSS group with reduced OTR expression reflects increased vulnerability, whereas the STSS with higher receptor expression may indicate an adaptive response conferring resilience [ 113 ].…”

Cerebral Immunohistochemical Characterization of the H2S and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma

“…Hydrogen sulfide (H 2 S), a gaseous mediator, and the oxytocin (OT)/oxytocin receptor (OTR) system are implicated in fluid homeostasis and may play a role in edema ( 7 ). Their interaction has been reported in trauma ( 8 , 9 ). In our porcine ASDH pilot study, markers of blood brain barrier (BBB) dysfunction and oxidative and nitrosative stress, were significantly elevated in the ipsilateral side, i.e., the side of ASDH induction.…”

“…Sections of ipsi- and contralateral brain specimens were analyzed concurrently, and negative controls were performed (examples see Figure S1 ). Since the IHC detection of OTR in the brain has proven to be a particular challenge in the past, the specificity of the OTR antibody used in this study was validated by both negative controls [knock out ( 9 )] and positive controls, western blot and immunoprecipitation (Proteintech, methods description and results in Figure S2 ). The specificity of the antibodies has been additionally confirmed in NCBI BLAST searches (courtesy of the U.S. National Library of Medicine).…”