Pharmacology and Toxicology

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Marilyn P. Merker, PhD

Professor
Yale University (1983)
PhD Pharmacology
VAMC
Cardiovascular Pharmacology
Phone: 414 384-2000 x41394
mmerker@mcw.edu
Dr. Merker's Faculty Collaboration Database

 


Research Interest

Endothelial cells, the cells that line blood vessels, carry out many functions, including metabolism of certain endogenous and pharmacological substances in the blood. The lung is a particularly important site of endothelial metabolic activity because there is an enormous blood perfused surface area composed of endothelial cells and because the lung receives the entire cardiac output. Therefore, the pulmonary endothelium is a predominant determinant of the composition of the blood reaching other organs.

Many different substances in the blood can be acted upon by the enzymes, receptors and transport proteins disposed on the luminal aspect of endothelial cells, including anesthetics and other centrally acting compounds, drugs that regulate blood pressure, endogenous vasoactive peptides, and potentially damaging oxidizing agents. The current research in this group is focused on the mechanisms regulating inactivation and activation of vasoactive peptides and the inactivation (reduction) of oxidizing substances.

One of the endothelial enzymes that plays a role in peptide metabolism is angiotensin converting enzyme (ACE). The action of ACE can result in peptide inactivation, as in the case of the vasodilator bradykinin, or activation, in the case of the vasoconstrictor, angiotensin II. Many peptide substrates for ACE contain the amino acid proline, and the prolyl peptide bond exists in two geometric conformations, either cis or trans. We have shown that only the trans conformer of the bond can act as an ACE substrate. Since the rate for the cis-trans isomerization is relatively slow compared to the transit time of the blood through the lungs, the trans conformers of the peptides are completely metabolized by ACE during the transit time of the blood through the lungs, but the cis conformers escape metabolism. We have hypothesized that the phenomenon may provide an explanation for the fact that a fraction of peptide that enters the lung survives passage through the lung to enter the general circulation. Since certain immunosuppressive drugs can affect peptide cis-trans isomerization rates, some of the cardiovascular side effects of these drugs may be due to their effects on the extent of peptide metabolism in the blood. For the studies of the influence of cis-trans isomerization on peptide metabolism we use intact perfused lung and bioassay preparations and high performance liquid chromatography to analyze the peptide metabolites. We also use partially purified enzymes for in vitro studies.

We have also recently discovered that the pulmonary endothelial plasma membrane contains a luminally disposed reducing enzyme that acts on oxidized substances in the blood. This enzyme may be important for protection of the lung or other organs from the detrimental effects of oxidants and may also be involved in the metabolism of certain drugs and endogenous compounds. We are particularly interested in the nature of its endogenous and pharmacological substrates, including anticancer drugs like doxorubicin and mitomycin C that undergo oxidation and reduction reactions that contribute to their therapeutic and side effects. Studies of the endothelial reductase are carried out using the intact perfused lung, endothelial cells in culture and partially purified endothelial membranes to characterize and further purify this enzyme. Some of the techniques involved are protein labelling procedures including biotinylation, affinity purification, and gel electrophoresis.


Recent Publications

Bongard RD, Krenz GS, Gastonguay AJ, Williams CL, Lindemer BJ, Merker MP: Characterization of the threshold for NAD(P)H:quinone oxidoreductase activity in intact sulforaphane-treated pulmonary arterial endothelial cells. Free Radic Biol Med 2011 50(8):953-62.

Gan Z, Audi SH, Bongard RD, Gauthier KM, Merker MP: Quantifying mitochondrial and plasma membrane potentials in intact pulmonary arterial endothelial cells based on extracellular disposition of rhodamine dyes.  Am J Physiol Lung Cell Mol Physiol. 2011 May;300(5):L762-72.

Lindemer BJ, Bongard RD, Hoffmann R, Baumgardt S, Gonzalez FJ, Merker MP: Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation.  Am J Physiol Lung Cell Mol Physiol. 2011 May;300(5):L773-80.

Bongard RD, Myers CR, Lindemer BJ, Baumgardt S, Gonzalez FJ, Merker MP: Coenzyme Q(1) as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung.  Am J Physiol Lung Cell Mol Physiol. 2012 May 1;302(9):L949-58.

Bongard RD, Yan K, Hoffmann RG, Audi SH, Zhang X, Lindemer BJ, Townsley MI, Merker MP: Depleted energy charge and increased pulmonary endothelial permeability induced by mitochondrial complex I inhibition are mitigated by coenzyme Q1 in the isolated perfused rat lung.  Free Radic Biol Med. 2013 Aug 1. doi:pii: S0891-5849(13)00384-5. 10.1016/j.freeradbiomed.2013.07.040. [Epub ahead of print]

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