Advisory Committee Chair
Shannon M Bailey
Advisory Committee Members
Jeannette E Doeller
Rakesh P Patel
Victor Darley-Usmar
Edward M Postlethwait
Giuseppe L Squadrito
Document Type
Dissertation
Date of Award
2012
Degree Name by School
Doctor of Philosophy (PhD) School of Public Health
Abstract
In recent years, hydrogen sulfide (H2S) has been identified as a ubiquitous cell signaling molecule. In addition to its diverse physiological roles, H2S has emerged as a possible drug therapy, with a wide range of applications. Along with cytoprotective effects in pathological states such as ischemia-reperfusion injury, H2S has been shown to decrease aerobic metabolism in a reversible manner. This dissertation is focused on exploring H2S-induced hypometabolism and the implications therein for human health and disease. We have shown that rats exposed to 80 ppm H2S gas in combination with low oxygen (10.5% O2) for 6 hr exhibit decreases in heart rate, breathing rate, and body temperature. H2S-dependent decreases in breathing rate and body temperature returned to base-line pre-exposure levels when rats were allowed to breathe room air for 1 hr. In contrast, heart rate remained depressed after the 1 hr recovery period at room air. To further explore this phenomenon, we modeled the hypometabolism seen in vivo with H2S in a cell culture system. Using rat primary hepatocytes and human hepatocellular carcinoma cells (Huh7), we found that H2S decreases oxygen consumption rate (OCR). Similar to what we have seen in vivo, this hypometabolic effect is reversible, with OCR returning to basal levels within 90 minutes. Additionally, the concentrations necessary to induce this hypometabolic state are not cytotoxic. We hypothesized that, in addition to O2 tension, sensitivity to H2S-induced hypometabolism is dictated by the activity of the enzymes responsible for the detoxification of H2S. Using small interfering RNAs (siRNA) we decreased levels of the mitochondrial sulfur transferase enzyme, rhodanese. Cells with decreased rhodanese expression were more sensitive to H2S-induced hypometabolism, displaying larger decreases in O2 consumption. We plan to further investigate the effect of H2S-induced hypometabolism on cellular bioenergetics by looking at ATP production in the presence of H2S and other inhibitors. Furthermore, we plan to explore the effects on other sources of energy production, such as glycolysis. In summary, the results presented in this dissertation show that H2S can induce a hypometabolic state. This hypometabolism is dependent on O2 tension and on the expression of H2S detoxifying enzymes.
Recommended Citation
Stein, Asaf, "The Hypometabolic actions of Hydrogen Sulfide in Mammalian Systems" (2012). All ETDs from UAB. 3032.
https://digitalcommons.library.uab.edu/etd-collection/3032