Abstract 19513: Cystathionine-gamma-lyase/hydrogen Sulfide is Critically Important for Ischemic Revascularization of Aged Mice
Introduction: Aging is a major risk factor for cardiovascular diseases (CVD) and is associated with complications including oxidative stress and inflammation. Hydrogen sulfide (H2S) and Nitric Oxide (NO) are gaseous signaling molecules implicated in numerous pathophysiological functions of the vasculature. CSE genetic deficiency and subsequent reduction in H2S levels attenuates ischemic vascular remodeling. Additionally, sirtuin1 (Sirt1) critically regulates mechanisms of angiogenesis, inflammation and cardioprotection. However, the importance of CSE/H2S in relation to age-dependent dysfunctions has not been investigated.
Objective: To investigate the age-dependent regulation of H2S and NO metabolites in aged mice and the rescue mechanisms mediated upon H2S therapy in aged mice ischemic hind limb model.
Methods: Unilateral femoral artery ligation was performed on 52-week-old CSE-/- mice, which were treated with PBS or H2S donor DATS (200μg/kg) administered retro-orbitally twice daily until Day 7. Hind limb perfusion was measured by laser Doppler flowmetry. Tissue angiogenic index and mature vessel density was determined by the ratios of CD31/DAPI and α-SMA/CD31 staining. SIRT1 expression was determined by immunohistochemistry and immunoblotting. Sulfide and NO metabolites were measured in various organs of 52-week-old CSE-/- mice. The monobromobimane (MBB)-HPLC method was used to measure free, acid labile sulfides and bound sulfane sulfur pools. NO metabolites, nitrite and X-NO, were measured using NO chemiluminescence.
Results: Ischemic hind limb perfusion was significantly impaired in 52-week-old CSE-/- compared to PBS control, while blood flow showed recovery in DATS treated cohorts by day 7 of ligation. Angiogenic index and mature blood vessel density was decreased in CSE-/- control mice, and increased with DATS treatment. DATS treatment also augmented NO metabolites compared to PBS treatment. Lastly, DATS significantly increased Sirt1 expression in ischemic tissues of CSE-/- mice.
Conclusion: Our study reveals a critically important role of CSE/H2S in age-associated ischemic revascularization. H2S play an important role in rescue mechanisms for ischemic revascularization of aged mice involving increased Sirt1.
Author Disclosures: G.K. Kolluru: None. S. Rajpal: None. S. Pardue: None. X. Shen: None. C.G. Kevil: Research Grant; Significant; NIH HL113303. Ownership Interest; Significant; Theravasc Inc, Innolyzer LLC.
- © 2014 by American Heart Association, Inc.