School of Medicine

Wayne State University School of Medicine

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Ye-Shih Ho, Ph.D.

The nature of glutaredoxin in oxidant-mediated tissue injury

Overproduction of reactive oxygen species (ROS) have been implicated as important pathogenic mediators in many clinical disorders such as hyperoxic lung injury and ischemia/reperfusion- and doxorubicin-induced cardiac damage. The function of the prototypic antioxidant enzymes, which include three isoforms of superoxide dismutase, catalase, and glutathione peroxidase, in protecting cells and animals against oxidant-mediated tissue injury has been studied quite extensively both in vitro in cultured cells and in vivo in a whole animal. However, the molecular and cellular mechanisms by which ROS cause tissue injury are not well understood. In other words, the biochemical and cellular pathways, that are initiated by the increased oxidative stress in the targeted tissues and that contribute to the injury, are not known. Since sulfhydryl proteins are targets for oxidative modification when cells are under oxidative stress, and inactivation of the catalytic functions of critical cellular proteins may lead to irreversible cellular damage, we hypothesize that oxidation of sulfhydryl groups of proteins may contribute to the pathogenesis of the above three models of oxidant-mediated injury. Toward this end, the current research in our laboratory is to define the role of the cytosolic and the mitochondrial isoforms of glutaredoxin (Grx1 and Grx2, respectively), a thiotransferase functioning in reductive cleavage of protein-glutathione mixed disulfides, in antioxidant defense using both transgenic and knockout mice. The potential cellular targets that interact with and that are protected by Grx1 and Grx2 will also be defined by proteomics approaches. 

 Targeting RhoA-mediated motor axonopathy for treatment of amyotrophic lateral sclerosis

 Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord. Similar to the neurons in the central nervous system (CNS), motor neurons do not naturally regenerate in adult humans. In models of CNS injury, axonal regeneration is prevented by a variety of inhibitory molecules in the extracellular milieu, such as chondroitin sulfate proteoglycans (CSPGs) and numerous myelin-derived proteins. Most of the signaling pathways activated by these inhibitors converge on RhoA GTPase, and inhibition of RhoA signaling significantly promotes axonal outgrowth in vitro in the presence of various inhibitory molecules and facilitates recovery from models of CNS injury in rodents. We found that RhoA is also activated in the spinal cords of G93A-SOD1 ALS mice. In light of the evidence, we hypothesize that RhoA activation participates in the pathogenesis of ALS. It is, therefore, a therapeutic target for ALS. We currently are interested in determining the mechanism by which RhoA is activated in the spinal cords of G93A-SOD1 mice, and whether blockade of RhoA activity by miRNA-based shRNA, CRISPR/cas-mediated gene disruption, and chemical inhibitors ameliorates the disease phenotypes of ALS mice.


Ph.D., Biological Sciences, Carnegie Mellon University, 1981

Transgenic mouse models, oxidative stress, antioxidant defense mechanism, amyotrophic lateral sclerosis

  • Adluri RS, Thirunavukkarasu M, Zhan L, Akita Y, Samuel SM, Otani H, Ho Y-S, Maulik G, Maulik N. Thioredoxin-1 enhances neovascularization and reduces ventricular remolding during chronic myocardial infarction: An insight with thioredoxin 1 transgenic overexpression mice. J Mol Cell Cardio 50:239–247, 2011. PMID: 21074540.
  • Aesif SW, Anathy V, Kuipers I, Guala AS, Reiss JN, Ho Y-S, Janssen-Heininger YM. Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced pulmonary inflammation and alveolar macrophage activation. Am J Respir Cell Mol Biol 44:491–499, 2011. PMID: 20539014.
  • Ivashchenko O, van Veldhoven PP, Brees C, Ho Y-S, Terlecky SR, Fransen M. Intraperoxisomal redox balance in mammalian cells: oxidative stress and interorganellar crosstalk. Mol Biol Cell 22:1440–1451, 2011. PMID: 21372177.
  • Wu H, Lin L, Giblin F, Ho Y-S, MF Lou MF. Glutaredoxin 2 knockout increases sensitivity to oxidative stress in mouse lens epithelial cells. Free Radic Biol Med 51:2108–2117, 2011. PMID: 21983434.
  • Hwang I, Lee J, Huh JY, Park J, Lee HB, Ho Y-S, Ha H. Catalase deficiency accelerates diabetic renal injury through peroxisomal dysfunction. Diabetes 61:728–738, 2012. PMID: 22315314.
  • Adluri RS, Thirunavukkarasu M, Zhan L, Dunna NR, Akita Y, Selvaraju V, Otani H, Sanchez JA, Ho Y-S, Maulik N. Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction. PLoS One 7:e34790, 2012. PMID: 22523530.
  • Hoffman SM, Tully JE, Lahue KG, Anathy V, Nolin JD, Guala AS, van der Velden JL, Ho Y-S, Aliyeva M, Daphtary N, Lundblad LK, Irvin CG, Janssen-Heininger YM. Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease. Am J Physiol Lung Cell Mol Physiol 303(6):L528–L538, 2012. PMID: 22752969.
  • Sakai J, Li J, Subramanian KK, Mondal S, Bajrami B, Hattori H, Jia Y, Dickinson BC, Zhong J, Ye K, Chang CJ, Ho Y-S, Zhou J, Luo HR. Reactive oxygen species-induced actin glutathionylation controls actin dynamics in neutrophils. Immunity 37:1–13, 2012. PMID: 23159440.
  • Jang JY, Min JH, Chae YH, Baek JY, Wang SB, Park SJ, Oh GT, Lee S-H, Ho Y-S, Chang T-S. Reactive oxygen species play a critical role in collagen-induced platelet activation via SHP-2 oxidation. Antioxid Redox Signal 20:2528–2540, 2014. PMID: 24093153.
  • Murdoch CE, Shuler M, Haeussler DJ, Kikuchi R, Bearelly P, Han J, Watanabe Y, Fuster JJ, Walsh K, Ho Y-S, Bachschmid MM, Cohen RA, Matsui R. Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. J Biol Chem 289:8633‒8644, 2014. PMID: 24482236.
  • Wu H, Yu Y, David L, Ho Y-S, Lou MF. Glutaredoxin 2 (Grx2) gene deletion induces early onset of age-dependent cataract in mice. J Biol Chem 289:36125‒36139, 2014. PMID: 25362663.
  • Mai HN, Chung YH, Shin EJ, Kim DJ, Jeong JH, Nguyen TT, Nam Y, Lee YJ, Nah SY, Yu DY, Jang CG, Ho Y-S, Lei XG, Kim HC. Genetic depletion of glutathione peroxidase-1 potentiates nephrotoxicity induced by multiple doses of cocaine via activation of angiotensin II AT1 receptor. Free Radic Res 50:467–483, 2016. PMID: 26930476.
  • Hoffman SM, Qian X, Nolin JD, Chapman DG, Chia SB, Lahue KG, Schneider R, Ather JL, Randall MJ, McMillan DH, Jones JT, Taatjes DJ, Aliyeva M, Daphtary N, Abdalla S, Lundblad LK, Ho Y-S, Anathy V, Irvin CG, Wouters EF, Reynaert NL, Dixon AE, van der Vliet A, Poynter ME, Janssen-Heininger YM.Ablation of glutaredoxin-1 modulates house dust mite-induced allergic airways disease in mice. Am J Respir Cell Mol Biol 55:377–386, 2016. PMID: 27035878.
  • Dzinic SH, Bernardo MM, Li X, Fernandez-Valdivia R, Ho YS, Mi QS, Bandyopadhyay S, Lonardo F, Vranic S, Oliveira DS, Bonfil RD, Dyson G, Chen K, Omerovic A, Sheng X, Han X, Wu D, Bi X, Cabaravdic D, Jakupovic U, Wahba M, Pang A, Harajli D, Sakr WA, Sheng S. An essential role of maspin in embryogenesis and tumor suppression. Cancer Res, In Press, 2017. PMID: 27923833.
Other Information
  • Postdoctoral Fellow, Howard Hughes Medical Institute, University of California at San Francisco, 1982 – 1985.
  • Postdoctoral Fellow, Howard Hughes Medical Institute, Duke University Medical Center, 1985 – 1987.
  • Assistant Medical Research Professor, Department of Medicine, Duke University Medical Center, 1987 – 1992.
  • Associate Professor, Institute of Chemical Toxicology, and Department of Biochemistry and Molecular Biology, Wayne State University, 1992 – 2000.
  • Professor, Institute of Environmental Health Sciences, and Department of Biochemistry and Molecular Biology, Wayne State University, 2000 – Present.