This report describes the progress of the research performed during the first 3.5 years of the R37 award. The research has focused on the protective and cytotoxic actions of nitric oxide in liver cells in two interrelated aims.
Under Aim I we proposed to determine how cellular redox status regulates the chemical fate and function of nitric oxide in hepatocytes. We have shown that the consequences of NO exposure on hepatocytes dependent on cell redox stress. We have also partially characterized denitrosation activityin liver cells. We have discoveredthat the inducible nitric oxide synthase (iNOS) translocates to the peroxisome in hepatocytes. This enzyme exhibits decreasedspecific activity. This may be a mechanism to shuttle dysfunctional enzyme out of the cell.
Under Aim II we determine how cyclic nucleotides prevent apoptosis. We have shown that cGMP and cAMP block the proximal events in apoptotic signaling. Furthermore, we have begun to explore novel and important areas in our research. Specifically, we have demonstrated that FADD levels increase dramatically in response to apoptotic stimuli. Furthermore, we have demonstrated that death inducing signaling complex (DISC) components translocate to the mitochondria during apoptotic signaling. TNF receptor also translocates to the mitochondria following TNF stimulation. These observations are described in the progress report. We also detail our plans to pursue these novel findings in the future.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Study Section
Special Emphasis Panel (NSS)
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Somers, Scott D
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University of Pittsburgh
Schools of Medicine
United States
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Zhang, Liyong; Xiang, Wenpei; Wang, Guoliang et al. (2016) Interferon β (IFN-β) Production during the Double-stranded RNA (dsRNA) Response in Hepatocytes Involves Coordinated and Feedforward Signaling through Toll-like Receptor 3 (TLR3), RNA-dependent Protein Kinase (PKR), Inducible Nitric Oxide Synthase (iNOS) J Biol Chem 291:15093-107
Scott, Melanie J; Billiar, Timothy R; Stoyanovsky, Detcho A (2016) N-tert-butylmethanimine N-oxide is an efficient spin-trapping probe for EPR analysis of glutathione thiyl radical. Sci Rep 6:38773
Deng, Meihong; Loughran, Patricia A; Zhang, Liyong et al. (2015) Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling. Sci Signal 8:ra11
Loughran, Patricia A; Stolz, Donna B; Barrick, Stacey R et al. (2013) PEX7 and EBP50 target iNOS to the peroxisome in hepatocytes. Nitric Oxide 31:9-19
Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna et al. (2012) cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes. Biochem Biophys Res Commun 423:85-90
Chanthaphavong, R Savanh; Loughran, Patricia A; Lee, Tiffany Y S et al. (2012) A role for cGMP in inducible nitric-oxide synthase (iNOS)-induced tumor necrosis factor (TNF) α-converting enzyme (TACE/ADAM17) activation, translocation, and TNF receptor 1 (TNFR1) shedding in hepatocytes. J Biol Chem 287:35887-98
Darwiche, Sophie S; Pfeifer, Roman; Menzel, Christoph et al. (2012) Inducible nitric oxide synthase contributes to immune dysfunction following trauma. Shock 38:499-507
Eum, Hyun-Ae; Vallabhaneni, Raghuveer; Wang, Yinna et al. (2011) Characterization of DISC formation and TNFR1 translocation to mitochondria in TNF-ýý-treated hepatocytes. Am J Pathol 179:1221-9
Nakao, Atsunori; Huang, Chien-Sheng; Stolz, Donna B et al. (2011) Ex vivo carbon monoxide delivery inhibits intimal hyperplasia in arterialized vein grafts. Cardiovasc Res 89:457-63
Cardinal, Jon S; Zhan, Jianghua; Wang, Yinna et al. (2010) Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney Int 77:101-9

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