Experimental evidence is emerging that the gasotransmitter hydrogen sulfide serves an important role in the cardiovascular system especially during tissue ischemia. However, specific cellular sources, targets, and mechanisms of hydrogen sulfide within the vasculature remain largely unknown. Work from our lab and others demonstrate that hydrogen sulfide is protective against chronic tissue ischemia, which involves increased vascular remodeling responses such as angiogenesis. Importantly, very little mechanistic information exists regarding how hydrogen sulfide modulates ischemic vascular remodeling in vivo or in vitro. Data in this application reveals a novel finding that hydrogen sulfide emanating from cystathionine !-lyase (CSE) selectively augments ischemic tissue nitrite reduction to NO that mediates increased angiogenic activity involving HIF-1"""""""" activity and VEGF expression. Experiments in this proposal will determine molecular mechanisms for these novel results through the hypothesis that endothelial cell CSE dependent hydrogen sulfide generation augments ischemic nitrite reduction to NO that increases ischemic vascular remodeling. The hypothesis will be examined through the pursuit of three specific aims including: 1) determine how endothelial cell CSE expression regulates ischemic vascular remodeling responses, 2) determine the mechanisms by which hydrogen sulfide increases NO generation in ischemic tissue and how this regulates HIF-1"""""""" activity and VEGF expression, and 3) determine the effect of endothelial cell CSE dependent hydrogen sulfide on diabetic ischemic vascular remodeling responses. Successful completion of this project will significantly advance the fields understanding of hydrogen sulfide biology in the vascular system, provide clear mechanistic information on hydrogen sulfide-NO pathway interactions, and identify novel approaches for ischemic vascular disease therapy.
Peripheral ischemic vascular disease (e.g. Peripheral Arterial Disease (PAD) is a chronic disorder associated with reduced blood flow to the extremities, which results in serious complications such as critical limb ischemia, limb amputation and in some cases may lead to death. Individuals with PAD suffer from endothelial cell dysfunction and lack of bioavailable nitric oxide (NO). Moreover, patients with diabetes are also at a greater risk of developing PAD. Work from our laboratory has discovered that hydrogen sulfide selectively increases endothelial cell NO bioavailability through a novel mechanism of nitrite reduction back to NO. Studies in this proposal will identify critical endothelial cell enzymes regulating hydrogen sulfide formation and subsequent NO formation. These results will identify novel molecular targets for potential therapeutic interventions directed at peripheral ischemic vascular disease.
|Kevil, Christopher G (2017) Catalase as a regulator of reactive sulfur metabolism; a new interpretation beyond hydrogen peroxide?. Redox Biol 12:528-529|
|Steiger, Andrea K; Pardue, Sibile; Kevil, Christopher G et al. (2016) Self-Immolative Thiocarbamates Provide Access to Triggered H2S Donors and Analyte Replacement Fluorescent Probes. J Am Chem Soc 138:7256-9|
|Yuan, Shuai; Pardue, Sibile; Shen, Xinggui et al. (2016) Hydrogen sulfide metabolism regulates endothelial solute barrier function. Redox Biol 9:157-166|
|Yuan, Shuai; Kevil, Christopher G (2016) Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Remodeling. Microcirculation 23:134-45|
|Montoya, Leticia A; Shen, Xinggui; McDermott, James J et al. (2015) Mechanistic investigations reveal that dibromobimane extrudes sulfur from biological sulfhydryl sources other than hydrogen sulfide†Electronic supplementary information (ESI) available: Experimental details, pH stability data for BTE, NMR spectra. See DOI Chem Sci 6:294-300|
|Kolluru, Gopi K; Bir, Shyamal C; Yuan, Shuai et al. (2015) Cystathionine ?-lyase regulates arteriogenesis through NO-dependent monocyte recruitment. Cardiovasc Res 107:590-600|
|Jiang, Zheng; Li, Chun; Manuel, Morganne L et al. (2015) Role of hydrogen sulfide in early blood-brain barrier disruption following transient focal cerebral ischemia. PLoS One 10:e0117982|
|Chen, Jie; Leskov, Igor L; Yurdagul Jr, Arif et al. (2015) Recruitment of the adaptor protein Nck to PECAM-1 couples oxidative stress to canonical NF-?B signaling and inflammation. Sci Signal 8:ra20|
|Li, Wenjuan; Zhang, Chunjing; Jackson, Kasey et al. (2015) UCP2 knockout suppresses mouse skin carcinogenesis. Cancer Prev Res (Phila) 8:487-91|
|Yuan, Shuai; Patel, Rakesh P; Kevil, Christopher G (2015) Working with nitric oxide and hydrogen sulfide in biological systems. Am J Physiol Lung Cell Mol Physiol 308:L403-15|
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