Abstract 17833: Role of 3-mercaptopyruvate Sulfur Transferase in Cardiac Ischemia/Reperfusion Injury

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Introduction: Hydrogen sulfide (H2S) is endogenously produced by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3MST). CSE contributes significantly to cardiac H2S and exerts protective roles in ischemia/reperfusion (I/R) injury and heart failure. Recently, 3MST has attracted significant attention as a source of H2S; however, its function in the heart remains unknown.

Hypothesis: 3MST localizes in the cytosol and mitochondria, a key organelle for energy production and cardiomyocyte survival. We, thus, investigated the role of 3MST in the setting of myocardial I/R injury.

Methods and Results: 3MST transcripts were 2.5-fold higher compared to CSE in the murine heart. 3MST was localized mainly in cardiomyocytes and smooth muscle cells. More than 60% of 3MST expressed in cardiomyocytes was co-localized with mito-tracker. Despite complete absence of 3MST protein, free H2S and sulfane sulfur levels were not different between 3MST KO and wild-type (WT) mice. 3MST KO exhibited no differences in heart rate, fractional shortening, ejection fraction, intraventricular septum length, left ventricular (LV) end-diastolic diameter, end-systolic diameter and posterior wall thickness. CBS, CSE, endothelial nitric oxide synthase and soluble guanylate cyclase were expressed to similar levels in 3MST KO and WT, while cGMP-dependent protein kinase was elevated in 3MST mice. Male, but not female, 3MST KO mice subjected to 30 min ischemia (LAD ligation) followed by 2 hrs of reperfusion exhibited reduced myocardial infarct size (29± 3% vs. 43 ± 3 %, p < 0.05 vs. WT). Similar observations were made when 3MST KO and WT mice were subjected to 45 min of myocardial ischemia followed by 24 hrs of reperfusion (Infarct Size 32 ± 5% vs. 52 ± 4 %, p < 0.01 vs. WT). Administration of the 3MST inhibitor I3MT-3 (10mg/kg, i.p., 1 hr prior the ischemia), exerted a similar cardioprotective effect. In addition, H9c2 infected with a 3MST adenovirus displayed increased cell death when exposed to H2O2 compared to the GFP-infected cells.

Conclusions: We conclude that 3MST, unlike CSE, negatively impacts cardiomyocyte survival following ischemia/reperfusion. Thus, 3MST inhibition may represent a novel target for cardioprotection.

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