Department of Biochemistry
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| Reto Asmis |
Reto Asmis, Professor & Director of Research Development (SHP)
| Education: | M.S. (Organic Chemistry), Ph.D. (Biochemistry), University of Fribourg, Switzerland |
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| Post Doctoral: | University of California at San Diego, University of Berne, Switzerland |
| Web Page: | |
| Email: | asmis@uthscsa.edu |
| Phone: | 567-2720 |
| Room: | DTL 5.210S |
THIOL REDOX SIGNALING AND CHRONIC INFLAMMATORY DISEASES
Chronic inflammatory diseases are associated with monocyte and macrophage dysfunction. Our laboratory studies novel molecular signaling mechanisms involved in monocyte/macrophage dysfunction and their role in dysregulated inflammatory processes, including atherosclerosis and other complications associated with metabolic diseases such as diabetes. We found that dysfunctional macrophages not only show increased levels of ROS formation, but they also accumulate mixed disulfides between protein thiols (PSH) and glutathione (GSH), a process referred to as protein S-glutathionylation. We could show that several features associated with monocyte/macrophage dysfunction, including dysregulated cytokine release and enhanced chemotaxis are mimicked by healthy cells that were exposed to oxidants that promote protein-S-glutathionylation. Emerging evidence suggest that S-glutathionylation/deglutathionylation represents a novel, redox-based signaling paradigm similar to phosphorylation/dephosphorylation. Our preliminary evidence supports the hypothesis that only specific proteins are targeted for S-glutathionylation, and depending on the oxidative insult, selected signaling pathways are attenuated. Our data suggest that enhanced protein-S-glutathionylation is a common feature in monocytes and macrophages dysfunction, but that different environments may promote different S-glutathionylation patterns. The goal of our research is aimed at understanding the mechanisms leading to enhanced protein-S-glutathionylation and at identifying proteins and their signaling pathways targeted for S-glutathionylation. To this end, we are developing new redox proteomics approaches. We also generated novel transgenic mice that overexpress either cytosolic glutaredoxin 1 (Grx1) or mitochondrial Grx2 in a macrophage-restricted manner. Glutaredoxins (thiol transferases) are small thiol-disulfide oxidoreductases that catalyze the reduction eduction of mixed disulfides between GSH and protein thiols. We therefore expect that monocytes and macrophages from these transgenic animals are more resistant to chronic (thiol) oxidative stress and cell dysfunction induced by a variety of metabolic environments. We currently focus on four projects:
1. Glutaredoxins in macrophage injury and the development and progression of atherosclerotic lesions.
2. Protein-S-glutathionylation in macrophage recruitment and diabetic complications.
3. Protein-S-glutathionylation and monocyte dysfunction in the development of lung cancer.
4. Monocytic Nox4: a novel NAD(P)H oxidase in monocyte differentiation, redox signaling and macrophage function.
Furthermore, we are interested in phytonutrients with anti-inflammatory properties that activate the cellular thiol antioxidant system and thus may protect monocytes against thiol oxidative stress and cell dysfunction. To this end, we are examining the effects of resveratrol and ursolic acid on accelerated atherosclerosis and renal injury in a new mouse model of diabetic complications.
Selected publications:
- Qiao M, Zhao Q, Fung Lee C, Tannock LR, Smart EJ, Lebaron RG, Phelix CF, Rangel Y, Asmis R
Thiol Oxidative Stress Induced by Metabolic Disorders Amplifies Macrophage Chemotactic Responses and Accelerates Atherogenesis and Kidney Injury in LDL Receptor-Deficient Mice.
Arterioscler Thromb Vasc Biol: 2009-07-10; (); Epub: 2009-07-10.
PMID: 19592463 - Qiao M, Kisgati M, Cholewa JM, Zhu W, Smart EJ, Sulistio MS, Asmis R
Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice.
Arterioscler Thromb Vasc Biol: 2007-06-01; 27(6); 1375-82 Epub: 2007-03-15.
PMID: 17363688 - Wang Y, Qiao M, Mieyal JJ, Asmis LM, Asmis R
Molecular mechanism of glutathione-mediated protection from oxidized low-density lipoprotein-induced cell injury in human macrophages: role of glutathione reductase and glutaredoxin.
Free Radic Biol Med: 2006-09-01; 41(5); 775-85 Epub: 2006-06-03.
PMID: 16895798 - Asmis R, Begley JG
Oxidized LDL promotes peroxide-mediated mitochondrial dysfunction and cell death in human macrophages: a caspase-3-independent pathway.
Circ Res: 2003-01-10; 92(1); e20-9
PMID: 12522131