Increased H2S availability, through use of H2S donors, or in mice overexpressing the H2S synthetic enzyme cystathionine gamma-lyase (CSE), reduces injury associated with myocardial ischemia (MI) and ischemia-reperfusion. The mitochondrial enzyme thiosulfate sulfurtransferase (TST) has a putative role in removal of H2S and inhibition may provide an alternative means of therapeutically increasing H2S bioavailability. This study investigated the hypothesis that deletion of TST in mice (Tst-/-) would reduce infarct size and improve outcome following MI.Methods
TST expression was assessed by qRT-PCR and Western blotting. Tst-/- and wild-type (WT) mice were anaesthetised for assessment of cardaic structure and function by high frequency ultrasound and for measurement of blood pressure. MI was induced by coronary artery ligation in vivo , or ex vivo in perfused hearts, when 30 mins ischemia was followed by 120 min reperfusion.Results
qRT-PCR and Western blots confirmed the presence of TST in the murine heart and also deletion in Tst-/-. Tst-/- mice survived to adulthood, had no change in blood pressure relative to WT and and had normal cardiac structure and function. Expression of the H2S synthesising enzyme, cystathionine gamma-lyase (CSE), was reduced in Tst-/- relative to WT hearts (n = 5, p < 0.01). Following MI the incidence of cardiac rupture was increased in Tst-/- mice (66%, vs 20% in WT). Studies in isolated hearts revealed increased infarct size in Tst-/- (88 ± 2% area at risk, vs 65 ± 6% in WT, n = 6, p = 0.01).Discussion
TST is present in the heart and deletion does not influence structure or function. Tst-/- mice have reduced cardiac CSE expression, suggesting reduced H2S synthetic capacity. This may underlie the increased susceptibility of Tst-/- mice to myocardial injury and increased mortality.Conclusion
TST may act with CSE to regulate H2S availability. Alteration in the balance of these enzymes has no overt physiological effect, but is associated with reduced capacity of the heart to resist ischaemic stress.Conclusion
This study was supported by a BHF 4 PhD studentship to BE and by a BHF Centre of Research Excellence Award.