Albert W. Girotti, Ph.D.

Professor

Dr. Girotti received his Bachelor of Science degree in Biology from Massachusetts Institute of Technology in 1959 and his Doctorate degree in Biochemistry from the University of Massachusetts, Amherst in 1965. He was a Postdoctoral Research Associate at Cornell University Medical College (1965-1968) where he investigated the role of metal ions in ribonuclease activity. Dr. Girotti joined the faculty of the Biochemistry Department at the Medical College of Wisconsin in 1968.

Contact Information

agirotti@mcw.edu
Phone: (414) 456-8432
Fax: (414) 456-6510

Research Interests

Aerobic cells may experience oxidative stress damage if their enzymatic and non-enzymatic antioxidant defenses are overwhelmed by reactive oxygen species (ROS) generated by various endogenous and exogenous challenges.  Unsaturated lipids in cell membranes and lipoproteins are prominent targets of ROS attack, undergoing peroxidative degradation with numerous structurally and functionally disruptive effects. Examples of free radical and non-radical ROS are shown in Scheme 1.

Among the many intermediates/products of lipid peroxidation, hydroperoxide species (LOOHs) are of special interest because of their relatively long lifetimes compared with free radical precursors or products.  Under redox-constrained conditions, LOOHs can accumulate steadily with stress duration and may perturb membrane structure/function because of their relatively polar nature.  However, in the presence of reductants and catalytic iron, LOOHs can undergo one-electron reduction with formation of oxyl (LO·) and epoxyallylic peroxyl (OLOO·) radicals, which exacerbate membrane damage by triggering chain peroxidation reactions (Scheme 1).  Counteracting this is two-electron reductive detoxification catalyzed, for example, by glutathione-dependent selenoperoxidases, GPx4 (also known as PHGPx) being the most prominent isotype.  Other LOOH pathways include inter-lipid transesterification and inter-membrane or membrane-lipoprotein translocation. 

The Girotti group specializes in LOOH formation, turnover, and redox signaling activity, the latter currently attracting widespread biological and biomedical interest.  Relatively low LOOH pressure may signal for upregulation of antioxidant proteins and activation of pro-growth transcription factors, whereas high LOOH pressure can signal for growth cessation and programmed cell death (apoptosis).  Ongoing projects in the Girotti laboratory include the following: (a) Selenoperoxidase-mediated LOOH metabolism and how this modulates the pathologic as well as therapeutic effects of oxidative stress - as in antitumor photodynamic therapy, for example; (b) the biological ramifications of spontaneous or transfer protein-facilitated LOOH translocation between membranes or membranes and lipoproteins; pioneering studies of this phenomenon were carried out in the Girotti laboratory; (c) Immediate and delayed protective effects of nitric oxide (NO) against peroxidative cell killing.  The latter studies focus on NO as a scavenger of lipid-derived free radicals on the one hand and inducer of antioxidant proteins such as heme oxygenase-1 and ferritin on the other.

Selected Publications

"Lipid and protein damage provoked by ultraviolet radiation: mechanisms of indirect photooxidative damage." A.W. Girotti, and P.U. Giacomoni  In: Biophysical and physiological effects of solar radiation on human skin (P.U. Giacomoni, ed.) Elsevier, Amsterdam. (2007)

"Tumor cell hyperresistance to photodynamic killing arising from nitric oxide reconditioning." M. Niziolek, W. Korytowski, and A.W. Girotti, SPIE Proceedings 6427, 642705, 1-9. (2007)

"Lipid transfer protein binding of unmodified natural lipids as assessed by surface plasmon resonance methodology." R.M. Kernstock, and A.W. Girotti, Anal. Biochem., 365, 111-121. (2007)

"Phospholipase action of platelet activating factor acetylhydrolase, but not paraoxonase-1, on long fatty acyl chain phospholipid hydroperoxides." T. Kriska, G.K. Marathe, J.C. Schmidt, T.M. McIntyre, and A.W. Girotti, J. Biol. Chem. 282, 100-108 (2007).

"Intracellular dissemination of peroxidative stress: internalization, transport and lethal targeting of a cholesterol hydroperoxide by SCP-2-overexpressing hepatoma cells." T. Kriska, V.V. Levchenko, W. Korytowski, B.P. Atshaves, F. Schroeder, and A.W. Girotti, J. Biol. Chem. 281, 23643-23651 (2006).

"Nitric oxide-induced resistance to lethal photooxidative damage in a breast tumor cell line. M. Niziolek, W. Korytowski, and A.W. Girotti, Free Radic. Biol. Med. 40: 1323-1331. (2006)

"Separation and quantitation of phospholipid hydroperoxide families using high-performance liquid chromatography with mercury cathode electrochemical detection. W. Korytowski, M. Niziolek, and A.W. Girotti, Anal. Biochem. 343: 136-142 (2005)

A thin-layer chromatographic method for determining the enzymatic activity of peroxidases catalyzing the two-electron reduction of lipid hydroperoxides." T. Kriska, and A.W. Girotti,  J. Chromatogr. B. 827: 58-64 (2005)

"Merocyanine 540-sensitized photokilling of leukemia cells: role of post-irradiation chain peroxidation of plasma membrane lipids as revealed by nitric oxide protection.", M. Zareba, M. Niziolek, W. Korytowski, and A.W. Girotti, Biochim. Biophys. Acta. 1722: 51-59 (2005).

"Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells.", T. Kriska, W. Korytowski, and A.W. Girotti, Arch. Biochem. Biophys. 433: 435-446 (2005).

"Sterol carrier protein-2-facilitated intermembrane transfer of cholesterol- and phospholipid-derived hydroperoxides.",. A. Vila, V.V. Levchenko, W. Korytowski and A.W. Girotti, Biochemistry 43: 12592-12605 (2004).

"Separation and quantitation of peroxidized phospholipids using high-performance thin-layer chromatography with tetramethyl-p-phenylenediamine detection.", T. Kriska and A.W. Girotti, Anal. Biochem. 327: 97-106 (2004).

"Role of lipid hydroperoxides in photo-oxidative stress signaling.", A.W. Girotti and T. Kriska, Redox. Signal. 6: 301-310 (2004).

"Chain-breaking antioxidant and cytoprotective action of nitric oxide on photodynamically stressed tumor cells.", M. Niziolek, W. Korytowski, and A.W. Girotti, Photochem.Photobiol. 78: 262-270 (2003).

"Nitric oxide inhibition of free radical-mediated lipid peroxidation in photodynamically treated membranes and cells.", M. Niziolek, W. Korytowski, and A.W. Girotti, Free Radic. Biol. Med. 34: 997-1005 (2003).

"Spontaneous transfer of phospholipid and cholesterol hydroperoxides between cell membranes and low-density lipoprotein: assessment of reaction kinetics and prooxidant effects.", A. Vila, W. Korytowski, and A.W. Girotti, Biochemistry 41: 13705-13716 (2002).

"Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5-aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4.", T. Kriska, W. Korytowski, and A.W. Girotti, Free Radic. Biol. Med. 33: 1389-1402 (2002).

"Spontaneous intermembrane transfer of various cholesterol-derived hydroperoxide species: kinetic studies with model membranes and cells.", A. Vila, W. Korytowski, and A.W. Girotti, Biochemistry 40: 14715-14726 (2001).

"Hyperresistance to cholesterol hydroperoxide-induced peroxidative injury and apoptotic death in a tumor cell line that overexpresses glutathione peroxidase isotype-4.", R. Hurst, W. Korytowski, T. Kriska, R.S. Esworthy, F.F. Chu, A.W. Girotti Free Radic. Biol. Med. 31(9): 1051-1065 (2001).

"Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms.", A.W. Girotti, J. Photochem. Photobiol. B. 63(1-3): 103-113 (2001).

"Inhibition of free radical-mediated cholesterol peroxidation by diazeneiumdiolate-derived nitric oxide: effect of release rate on mechanism of action in a membrane system", W. Korytowski, M. Zareba, and A.W. Girotti, Chem. Res. Toxicol. 13: 1265-1274 (2000).

"Dissemination of peroxidative stress via intermembrane transfer of lipid hydroperoxides: model studies with cholesterol hydroperoxides", A. Villa, W. Korytowski, and A.W. Girotti, Arch. Biochem. Biophys., 380: 208-218 (2000).

"Nitric oxide inhibition of free radical-mediated cholesterol peroxidation in liposomal membranes", W. Korytowski, M. Zareba, and A.W. Girotti, Biochemistry 39: 6918-6928 (2000).

"Cholesterol as a singlet oxygen detector in biological systems", A.W. Girotti and W. Korytowski, Methods Enzymol., 319: 85-100 (2000).

"Radiolabeled cholesterol as a reporter for assessing one-electron turnover of lipid hydroperoxides", W. Korytowski, M. Wrona, and A.W. Girotti, Anal. Biochem., 270: 123-132 (1999).

"Singlet oxygen adducts of cholesterol: Photogeneration and reductive turnover in membrane systems", W. Korytowski and A.W. Girotti, Photochem. Photobiol., 70: 484-489 (1999).

"Lipid hydroperoxide analysis by high performance liquid chromatography with mercury cathode electrochemical detection", W. Korytowski, P.G. Geiger, and A.W. Girotti, Methods Enzymol., 300: 23-33 (1999).

"Lipid hydroperoxide generation, turnover, and effector activity in biological systems", (Review) A.W. Girotti, J. Lipid Res., 39: 1529-1542 (1998).