Carl A. Gruetter, Ph.D., Professor
Phone: (304)696-7316
Fax: (304)696-7391
E-mail: gruetter@marshall.edu
Office: MEB G33
Department of Pharmacology, Physiology and Toxicology
Joan C.Edwards School of Medicine
1542 Spring Valley Drive
Huntington, WV, 25704
Current Projects
-
Role of histamine in vascular smooth muscle cells. Although long-known to be present in blood vessels, non-mast cell histamine has received little investigation over the years as a potential factor involved in regulation of the vascular system. In view of extensive evidence suggesting multiple important roles for histamine in vascular physiology and pathophysiology, the goal of this project is to determine the function of the endogenous histaminergic system in vascular cells. Currently, research is aimed at elucidating regulatory mechanisms of histamine synthesis/metabolism and the function of histamine and/or its metabolites in vascular smooth muscle and endothelial cells. This research involves: 1) immunocytochemistry, Western blot and qualitative and quantitative PCR to investigate regulation of expression of histamine synthetic and metabolic enzymes; 2) enzyme activity measurements to assess post-translational regulation of the histamine synthetic and metabolic enzymes; 3) enzyme activity measurements to assess the capacity of histamine and/or its metabolites to interact with and regulate heme-containing enzymes; 4) manipulation of histamine synthesis/metabolism and measurement of appropriate cellular responses to determine potential roles(s) of histamine and/or its metabolites to regulate cell function. Results from this research should establish a basic role for the endogenous histaminergic system in the regulation of vascular cell function and provide the groundwork for future studies aimed at determining its involvement in cardiovascular diseases.
-
Role of histamine in cancer. Up-regulation of histamine content and expression/activity of the histamine forming enzyme, histidine decarboxylase (HDC) has been well documented in numerous cancer tissues/cells including: melanoma and breast cancer. However, the under lying mechanisms and roles of the endogenous histaminergic system in cancer progression remain unclear. This project will investigate the potential intracellular action of endogenous histamine and/or its imidazole metabolites to promote cancer cell invasiveness. Immunocytochemistry, Western blot and RT-PCR will be used to establish/verify the presence of HDC and histamine in selected melanoma and breast cancer cell lines. The role of endogenous histamine and/or its metabolites on invasiveness will be evaluated by measuring the effects of HDC blockade on invasiveness of cultured cells. Involvement of the NO/cGMP signaling pathway in histamine-related modulation of invasiveness will be evaluated and the potential synergistic interaction between hypoxia and the endogenous histaminergic system to promote invasiveness will be assessed.. It is anticipated that the results from this investigation will establish an important role for the endogenous histaminergic system to promote invasiveness in melanoma and breast cancer cells.
-
Regulation of heme-containing enzymes by histamine and its imidazole metabolites. Evidence suggests an interaction of histamine and/or its imidazole metabolites with heme-Fe as a mechanism through which the intracellular histaminergic system can regulate cellular function. Histamine and its major metabolites are imidazoles and numerous studies have demonstrated modulation of activity of heme-based enzymes by exogenous imidazole compounds. However, none of these previous studies were conducted toward determining a potential role for histamine and/or its metabolites in regulating cell function through an interaction with heme-based enzymes. This project tests the hypotheses that: a) histamine and/or its imidazole metabolites regulate activity of selected heme-containing enzymes (guanyly cyclase and nitric oxide synthase); and that modulation of intracellular histamine concentration regulates activity of the selected heme-containing enzymes in intact cells. These hypotheses will be tested using spectrophotometry to determine the interaction of histaminergic imidazoles with the heme moieties in the enzymes and by measuring the effects of altered histamine/imidazole metabolite concentrations on enzyme activity using purified enzymes and intact cultured cells. The results from this study should establish a basic mechanism through which intracellular imidazoles can affect cell function.
Publications
Tippens AS, Davis SV, Hayes JR, Bryda EC, Green TL, Gruetter CA. Detection of histidine decarboxylase in rat aorta and cultured rat aortic smooth muscle cells. Inflamm Res 53:390-395, 2004. Epub Aug 10, 2004
Tippens AS, Gruetter CA. Detection of histidine decarboxylase mRNA in human vascular smooth muscle and endothelial cells. Inflamm Res. 53:215-216, 2004. Epub May 12, 2004.
Gruetter CA, Bailey B, Easterling L, Szarek JL. A23187 induces release of histamine from isolated rat aorta. Life Sci 70:1709-1717, 2002.
Gruetter CA, Lemke SM, Valentovic MA, Szarek JL. Evidence that histamine is involved as a mediator of endothelium-dependent contraction induced by A23187 in bovine intrapulmonary vein. Eur J Pharmacol 257:275-283, 1994.