The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis

Abstract

The pathophysiology of sepsis-induced myocardial dysfunction is not resolved to date and comprises inflammation, barrier dysfunction and oxidative stress. Disease-associated reduction of tissue cystathionine-γ-lyase (CSE) expression, an endogenous H 2 S-producing enzyme, is associated with oxidative stress, barrier dysfunction and organ injury. CSE-mediated cardio-protection has been suggested to be related the upregulation of oxytocin receptor (OTR). CSE can also mediate glucocorticoid receptor (GR) signaling, which is important for normal heart function. A sepsis-related loss of cardiac CSE expression associated with impaired organ function has been reported previously. The aim of this current post hoc study was to investigate the role of cardiac GR and OTR after polymicrobial sepsis in a clinically relevant, resuscitated, atherosclerotic porcine model. Anesthetized and instrumented FBM (Familial Hypercholesterolemia Bretoncelles Meishan) pigs with high fat diet-induced atherosclerosis underwent poly-microbial septic shock (n = 8) or sham procedure (n = 5), and subsequently received intensive care therapy with fluid and noradrenaline administration for 24 h. Cardiac protein expression and mRNA levels were analyzed. Systemic troponin, a marker of cardiac injury, was significantly increased in septic animals in contrast to sham, whereas OTR and GR expression in septic hearts were reduced, along with a down-regulation of anti-inflammatory GR target genes and the antioxidant transcription factor NRF2. These results suggest a potential interplay between GR, CSE, and OTR in sepsis-mediated oxidative stress, inflammation and cardiac dysfunction.

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

“…This supports our findings of OTR and OT expression around the microvasculature in the ipsilateral hemisphere (see Figures 1A,C ). These findings well agree with our previous results of the interaction between H 2 S and the OT/OTR systems ( 8 , 39 ): OTR and CBS were both upregulated as a response to pressure induced injury, whereas CSE showed the inverse response. Noteworthy, CSE, CBS, OTR and OT, all showed expression at the base of the sulci in the ipsilateral side, where maximal pressure-induced stress occurs in the gyrencephalic brain (see Figure 1 ).…”

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

“…Downstream signaling cascades involved in mediating H 2 S-dependent vaso-active effects activate K ATP -channels and stimulate Akt-dependent endothelial eNOS. Furthermore, H 2 S can induce antioxidant effects via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which can be also regulated by OT [ 7 , 45 , 46 , 47 ]. H 2 S administration in rodents ameliorated myocardial fibrosis and oxidative stress in hypertension [ 48 ], and had beneficial effects on a myocardial infarct [ 15 , 49 , 50 , 51 , 52 ].…”

“…Subcutaneous OT administration in myocardial infarct resulted in reduced inflammation, apoptosis, and ultimately ameliorated heart function [ 79 , 80 , 81 , 82 ]. Finally, downregulation of the OT system is associated with dilated cardiomyopathy [ 83 ], hypertension [ 84 ] and impaired cardiovascular function [ 19 , 46 , 68 , 80 ]. In a porcine myocardial infarct model, placebo-treated animals with high endogenous OT levels at the start of the experiment had better ejection fraction overall compared to OT-treated animals with high basal endogenous OT levels [ 85 ].…”

“…Impaired endogenous H 2 S release is reported to be a key mediator with regard to the development of chronic cardiovascular pathology [ 8 ]. In a clinically relevant resuscitated model of septic shock, familial hypercholesterolemia Bretoncelles Meishan (FBM) swine, a comorbid large animal strain characterized by a clinical phenotype resembling the human atherosclerotic patient [ 90 , 91 ] with coronary artery disease, presented with elevated nitrotyrosine formation, a marker of nitrosative and oxidative stress, and significantly lowered CSE and OTR protein expression levels in the myocardium, which coincided with altered cardiac function [ 41 , 46 ]. Interestingly, already without septic shock, the FBM pig strain displayed decreased CSE expression in the media of the coronary artery and elevated nitrotyrosine formation [ 40 ].…”

Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation

“…In general, GR downregulation is reported to be associated with organ dysfunction in humans and different animal models, in particular in the liver [ 75 ], the heart [ 76 ], and the lung [ 77 ]. Vice versa, in swine with pre-existing coronary artery disease that underwent hemorrhagic shock (HS) and resuscitation, treatment with sodium thiosulfate (Na 2 S 2 O 3 ) during the first 24 h of resuscitation attenuated the impairment of lung mechanics and gas exchange, which coincided with higher lung tissue GR expression (as assessed by western blotting and immunohistochemistry, Fig.…”