Abstract 17877: Overexpression of the H2S Producing Enzyme Cystathionine gamma-Lyase in Endothelial Cells Ameliorates Myocardial Ischemia/Reperfusion Injury
Background: Hydrogen sulfide (H2S) donors protect against acute myocardial ischemia/reperfusion (MI/R) injury. Cystathionine gamma-lyase (CSE) is one of three H2S producing enzymes that regulate H2S bioavailability. We have previously demonstrated that overexpression of CSE in myocardium protects against MI/R injury.
Objective: The purpose of this study was to investigate if endothelial cell restricted overexpression of CSE protects the myocardium against I/R injury.
Methods and Results: Endothelial cell specific CSE transgenic (EC-CSE Tg) mice were generated by crossing the mice carrying the CSE gene driven by tetracycline response element to the mice with VE-Cadherin-driven tTA gene. EC-CSE Tg mice and tTA control mice (n = 7-9 per group) were sacrificed. Plasma free H2S level were determined with gas chromatography and sulfur chemiluminescence (Aligent). Significantly elevated plasma free H2S level were observed in EC-CSE Tg mice (0.28 ± 0.02 vs. 0.15 ± 0.04 μM, p < 0.05). EC-CSE Tg mice, tTA control mice, and wildtype (WT) mice (n = 8-10 per group) were subjected to 45 min of MI and 24 h of R. Blood was collected for troponin-I measurements at 4h of reperfusion. The EC-CSE Tg mice had significantly attenuated infarct size compared to the tTA control and WT mice (23.8 vs. 44.0 vs. 45.5 %, p < 0.05 vs. tTA control and WT). Circulating cardiac troponin-I was also significantly reduced in EC-CSE Tg mice compared to tTA control and WT mice (7.13 vs. 16.83 vs. 17.14 ng/ml, p < 0.05 vs. tTA control and WT).
Conclusion: Endothelial cell restricted genetic overexpression of CSE exerts significant protective effects in the setting of MI/R injury, suggesting that endothelial cell generated H2S may be a potential therapy for treating cardiovascular disease. Experiments are currently underway to define the mechanisms by which endothelial cell derived H2S protects the ischemic myocardium and the failing heart.
Author Disclosures: Z. Li: None. C.L. Organ: None. E. Donnarumma: None. C.M. Zibilich: None. J.W. Elrod: None. D.J. Lefer: None.
- © 2016 by American Heart Association, Inc.