Table 1.
Summary of animal studies: effects of stress/trauma/comorbidity and treatment on the cardiovascular system, H2S system and the OT/OTR system.
| Author and Year | Species | Type of Stress/Trauma/Comorbidity/Treatment | Read Out (Cardiovascular/H2S/OT/OTR) |
|---|---|---|---|
| Physical | |||
| Trautwein et al., 2021 [5] | Mice | naïve ΔMST animals Hemorrhagic Shock wt Hemorrhagic Shock & Blunt Chest Trauma wt |
Constitutive CSE & OTR in cardiomyocytes CSE & OTR↓ CSE & OTR↓ CSE &OTR↓↓ |
| Merz et al., 2020 & Nußbaum et al., 2016 [10,31] | Swine (hypercholesteremic) | Septic Shock (vs. sham animals) |
Systemic Troponin↑ ↓ cardiac output CSE & OTR↓ |
| Merz et al., 2018 [9] | Mice CSE−/− (vs. wt) |
native wt Blunt Chest Trauma (& cigarette smoke exposure (CS)) Blunt Chest Trauma CSE−/− (& CS) Blunt Chest Trauma CSE−/−& GYY4137 administration (& CS) |
Constitutive OTR in cardiomyocytes OTR↓ OTR↓↓ OTR↑↑ |
| Meng et al., 2015 [24] | Rats | Physical Myocardial Ischemia/Reperfusion Injury GYY4137 administration |
Myocardial Ischemia/Reperfusion led to: ↑CSE mRNA expression in the myocardium ↓CSE activity in the myocardium GYY4137 administration led to: ↓CSE mRNA expression in the myocardium ↑CSE activity in the myocardium ↑cardiac ejection fraction ↑fractional shortening ↓ischemia area alleviated histological injury ↓oxidative stress ↓apoptosis |
| Merz et al., 2017 [30] | Swine (hypercholesteremic vs. young german) | Septic Shock (vs. sham animals) |
Acute circulatory failure Coronary Arteries: ↓CSE in the media No CBS in the media; but localized to the adventitia and atheromatous plaques No 3MST |
| Mani et al., 2013 [41] | Mice CSE−/− (vs. wt) |
Knock out & atherogenic diet NaHS administration |
Early fatty streak lesions in the aortic root ↑Plasma levels of cholesterol & low-density lipoprotein cholesterol Hyperhomocysteinemia ↑ Lesional oxidative stress and adhesion molecule expression ↑Aortic intimal proliferation CSE−/− treated with NaHS: inhibited the accelerated atherosclerosis development |
| Kobayashi et al., 2009 [42] | Rabbit | Myocardial Ischemia/Reperfusion Injury | Postinfarct treatment with OT led to: ↑Left ventricular function & remodeling ↓Infarct size OTR↑ |
| Authier et al., 2010 [43] | Swine | Myocardial Infarct | Swine treated with OT immediately after the myocardical infarct for up to seven days: ↓Fraction shortening & no effect on lesion size 8d post myocardial infarct: swine with ↑basal endogenous OT levels receiving OT treatment: ↓Ventricular function & ↑infarct size 28 d post myocardial infarct: in comparison to placebo animals with ↑endogenous OT levels, swine with ↓endogenous OT: ↓infarct size OT administration led to: ↓Cardiac OTR in ↑endogenous OT animals, but not in ↓endogenous OT animals |
| Klein et al., 2018 [44] | Rats | Nutrient insufficiency in neonates | OTR-rich brain regions show: NF-kB was retained ↑ in the cortex, striatum nuclei, and medial preoptic nucleus NF-kB was ↓ & unchanged in nucleus of the solitary tract, paraventricular nucleus, and supra-optic nucleus Unprimed by colostrum: ↑Endoplasmic reticulum stress in solitary tract Primed by colostrum: ↓Endoplasmic reticulum stress in solitary tract |
| Iseri et al., 2005 [45] | Rats | Sepsis (vs. sham animals) |
Sepsis led to: ↑Malondialdehyde (indicating lipid peroxidation in colon, uterine & liver ↓Glutathione (key antioxidant) in colon & uterine ↑Myeloperoxidase (indicating neutrophil infiltration) in colon & liver ↑Collagen levels in the uterus & liver ↑serum TNF-α levels Subcutaneous OT treatment reversed the above negative effects induced by sepsis, while hepatic glutathione levels were not affected |
| Tain et al., 2016 [46] | Rats | Pregnant maternal suramin treatment |
Induced programmed hypertension in male offspring ↑Plasma nitric oxide synthase inhibitor (ADMA) Maternal n-acetylcysteine administration prevented hypertension Protective effects of n-acetylcysteine: ↑Plasma glutathione level, ↑3MST, & restoration of suramin-induced reduction in H2S synthesis in the kidneys |
| Tai et al., 2016 [47] | Rats | High-fat diet from weaning on/prenatal dexamethasone | Prenatal dexametahsone and postnatal high-fat diet induced programmed hypertension in adult offspring Prevented by maternal n-acetylcysteine therapy ↑gene expression of H2S-generating enzymes ↑Renal 3MST protein levels and activity ↑Plasma glutathione level, ↓oxidative stress |
| Petersson et al., 1997 [48] | Rats | Spontaneously hypertensive, subcutaneous OT or saline for 5 days to ♂ and ♀ rats |
♂: ↓blood pressure, no effect on heart rate, (vs. saline-treated controls), effect was gone 3d after the last injection ♀: no effect on blood pressure and heart rate |
| Melnik et al., 2017 [49] | Rats | Castrated | Castration in ♂ led to:↓CSE, ↓H2S, ↑proliferation, polyploidization & apoptosis in myocardium (vs. ♀) Castration in ♀ led to: ↑CSE, ↑H2S, ↓proliferation, polyploidization & apoptosis in myocardium (vs. ♂) |
| Lozic et al., 2014 [50] | Rats | Air-jet (overesxpressing OTR in paraventricular nucleus vs. sham) Pretreatment of OTR overexpressing rats with OT |
At baseline conditions: rats overexpressing OTR: ↑baroreceptor reflex sensitivity, ↓blood pressure variability (vs. sham) Exposure to stress: ↑blood pressure, blood pressure variability & heart rate in all rats Sham animals: ↓baroreceptor reflex sensitivity during stress Pretreatment of OTR overexpressing rats with OT: ↓baroreceptor reflex sensitivity, ↑blood pressure and heart rate variability (baseline and stress) Pretreatment of sham rats with OT: ↓baroreceptor reflex sensitivity, ↑blood pressure variability (baseline and stress) only ↑ heart rate variability during stress |
| Garrott et al., 2015 [51] | Rats | Left ventricular hypertrophy, heart failure, OT treatment |
Activation of hypothalamic OXT neurons to elevate parasympathetic tone let to: ↓cellular hypertrophy, IL-1β & fibrosis with OT treatment: Cardiac contractility parameters were significantly ↑ Heart rate sensitivity to β-adrenergic stimulation was ↑ |
| Psychological | |||
| Wigger et al., 2020 [8] | Mice | Maternal Separation (Early Life Stress) LTSS (long) STSS (short) |
CSE & OTR↓↓ CSE↓ & OTR↑↑ |
| Peters et al., 2014 [52] | Mice | Chronic psychosocial stress: chronic subordinate colony housing Infusion of OT (intracerebroventricular for 15 days) high and low dose |
High dose OT led to: anxiogenic phenotype, OTR binding in septum, amygdala & median raphe nucleus low dose OT led to: prevents hyper-anxiety, thymus atrophy, adrenal hypertrophy & ↓adrenal ACTH sensitivity (in vitro) |
| Wsol et al., 2008 [53] | Rats | Alarming stressor (air jet) Animals received intracerebroventricular: vehicle, OT, or OT-antagonist |
Under resting conditions: infusions no effect on cardiovascular parameters alarming stressor evoked: ↑mean arterial blood pressure ↑heart rate Animals that received the OT antagonist (vs. OT and vehicle treated): ↑↑mean arterial blood pressure ↑↑heart rate |
| Li et al., 2016 [54] | Mice | Maternal separation (vs. control without maternal separation) | Maternal separation led to changes in the proximal colon: ↓crypt lengths, ↓goblet cells per crypt, ↓glutathione peroxidase activity, ↑expression of thiobarbituric acid reactive substances & inducible nitric oxide synthase mRNA, ↑IL-6, TNFα & myeloperoxidase Administration of NaHS led to: ↓↓negative effects |
| Liu et al., 2017 [55] | Rats | Chronic unpredictable mild stress |
↑Depressive-like behavior, ↑hippocampal endoplasmic reticulum stress & ↓Sirt-1 NaHS administration led to: ↓Depressive-like behaviors, ↓hippocampal endoplasmic reticulum stress & ↑Sirt-1 |
Abbreviations: H2S = hydrogen sulfide; OT = oxytocin; OTR = oxytocin receptor; CSE = cystathionine γ-lyase; 3MST = 3-mercaptopyruvate sulphurtransferase; ΔMST = genetic mutation of 3MST; CS = cigarette smoke exposure; CBS = cystathionine β-synthase; NaHS = Sodium hydrosulfide; wt = wild type; CSE−/− = CSE knock out; ACTH: adrenocorticotropic hormone. ↓ slightly down, ↓↓ strongly down, ↑ slightly up, ↑↑ strongly up.