Cardiovascular disease and resuscitated septic shock lead to the downregulation of the H2S-producing enzyme cystathionine-γ-lyase in the porcine coronary artery

Abstract

BackgroundDownregulation of the hydrogen sulfide (H2S)-producing enzymes cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and/or 3-mercaptopyruvate sulfurtransferase (3-MST) is associated with chronic cardiovascular pathologies. Nevertheless, equivocal data are available on both the expression and function of these enzymes in coronary arteries (CA). We recently reported that atherosclerotic pigs subjected to sepsis developed impaired cardiac function, which coincided with decreased myocardial CSE expression and increased nitrotyrosine formation. To define the endogenous source(s) of H2S in the CA, we studied the expression of CBS, CSE, or 3-MST in the CA of pigs subjected to septic shock with/without pre-existing cardiovascular co-morbidity.MethodsAnesthetized and instrumented FBM "familial hypercholesterolemia Bretoncelles Meishan" pigs with high-fat diet-induced hypercholesterolemia and atherosclerosis were subjected to polymicrobial septic shock, or sham procedure, and subsequent intensive care therapy for 24 h. Young German domestic pigs were used as naïve controls. CSE, CBS, 3-MST, HO-1, eNOS, and nitrotyrosine expression was quantified by immunohistochemistry of formalin-fixed paraffin sections.ResultsFBM pigs, in the absence of septic shock, showed decreased CSE expression in the media. This decrease became more pronounced after sepsis. The expression pattern of HO-1 resembled the pattern of CSE expression. CBS protein was not detected in the media of any of the CA examined but was localized to the adventitia and only in the atheromatous plaques containing foam cells of the CA, in regions that also displayed abundant nitrotyrosine formation. The CBS expression in the adventitia was not associated with nitrotyrosine formation. 3-MST expression was not found in any of the CA samples.ConclusionsWe hypothesize that (i) the reduced CSE expression in FBM pigs may contribute to their cardiovascular disease phenotype and moreover (ii) the further decrease in CA CSE expression in sepsis may contribute to the sepsis-associated cardiac dysfunction.

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

“…Genetic CSE deletion led to a pronounced loss of OTR protein expression concomitant with reduced VEGF and AVPR expression. Although the exact mechanisms must be further investigated, our study suggests that cardiac CSE and OTR may interact in cardiovascular (dys)function [ 10 , 18 , 37 , 49 ].…”

“…In mice, the genetic deletion of cystathionine-γ-lyase (CSE; CSE −/− ) leads to hypertension [ 6 , 7 ], and OT knock-out mice (OT −/− ) are characterized by lower baseline but higher stress-induced blood pressure than wildtype (WT) animals [ 8 ]. The heart is known to express CSE [ 9 , 10 ], and both OT as well as the OT receptor (OTR) [ 11 ]. The oxytocin system has protective effects in myocardial I/R injury [ 12 – 15 ], and its downregulation is implicated in dilated cardiomyopathy [ 16 ], and hypertension [ 17 ], suggesting that reduced levels of OTR may aggravate these pathologies [ 18 ].…”

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…Fifth, they may become less effective when the endogenous H 2 S-producing enzymes are inhibited or downregulated. In fact, several pathophysiological states (e.g., Aminzadeh and Vaziri, 2012;Guo et al, 2012;Holwerda et al, 2012;Wang et al, 2014a;Huang et al, 2017;Merz et al, 2017) as well as various pharmacological agents, e.g., dexamethasone (d'Emmanuele di Villa Bianca et al, 2015), can induce the downregulation of CBS or CSE, while 3-MST is oxidation-prone and can be inactivated in various pathophysiological states, for instance diabetes mellitus (Coletta et al, 2015). Sixth, these molecules are not novel structures nor proprietary, therefore they are of limited interest to develop them commercially.…”

The Role of Hydrogen Sulfide on Cardiovascular Homeostasis: An Overview with Update on Immunomodulation

“…Meanwhile, the three H 2 S-generating enzymes have been broadly localized in cardiovascular system ( Pan et al, 2012 ). Downregulation of the three H 2 S-producing enzymes is associated with chronic cardiovascular pathologies ( Kanagy et al, 2017 ; Merz et al, 2017 ). Unfortunately, the H 2 S-producing enzymes responsible for H 2 S production and biological function in cardiovascular homeostasis are not clear and consistent in current literature ( Kuo et al, 2016 ; Li et al, 2016 ).…”