Phillip G. Kopf, PhD
University of New Mexico (2008)
PhD Biomedical Sciences
Department of Pharmacology
Chicago College of Osteopathic Medicine
Elevated circulating aldosterone levels are associated with hypertension, thrombosis formation, cardiac hypertrophy, and congestive heart failure. Aldosterone secretion is regulated by angiotensin II (Ang II), potassium, and adrenocorticotropic hormone (ACTH). I am interested in the underlying mechanisms of aldosterone secretion with the goal to address the development and progression of hyperaldosteronism. I currently have two research projects in this area that examine aldosterone secretion with two distinctive approaches: a pharmacological approach and a toxicological approach.
The role of 12-lipoxygenase in aldosterone secretion. Ang II stimulation of aldosterone secretion is mediated by AT1 receptors and phospholipase C-calcium downstream signaling. Evidence exists for an essential role of the 12-lipoxygenase (12-LO) pathway in Ang II-stimulated aldosterone secretion. However, the identity of 12-LO metabolites, as well as the mechanism and extent by which these metabolites contribute to Ang II-stimulation of aldosterone secretion remains unknown. The goal of our studies is to understand the role of 12-LO in the regulation of aldosterone secretion. Our current data indicates that endogenous production of 12-LO metabolites are produced by adrenal zona glomerulosa (ZG) cells and that a novel stereoselective G protein-coupled receptor (GPCR) is present on ZG cell plasma membranes. Identification of the 12-LO metabolites and the receptor that mediates aldosterone secretion would provide a novel pharmacological target for the remediation of circulating aldosterone levels.
Polybrominated diphenyl ethers (PBDEs) and steroidogenesis. PBDEs are widely used flame retardants. PBDEs leach into the environment, bioaccumulate, and are detected in U.S. breast milk samples. Some of these PBDEs upregulate enzymes involved in steroidogenesis in a human adrenocortical cell line. With growing evidence supporting a role for environmental pollutants in the development of cardiovascular disease, an investigation into the potential role of these PBDEs in the alteration of aldosterone synthesis is warranted. Our current data suggest that PBDEs induce aldosterone secretion from cultured ZG cells in a concentration-dependent manner. Future studies will further characterize this response and determine if chronic PBDE exposure results in hyperaldosteronism.
Kopf, PG, Gauthier, KM, Zhang, DX, Falck, JR, and Campbell, WB. 2011. Angiotensin II Regulates Adrenal Vascular Tone Through Zona Glomerulosa Cell-Derived EETs and DHETs. Hypertension. 57:323-329.
Kopf, PG, Scott, JA, Agbor, LN, Boberg, J, Elased, KM, Huwe, JK, and Walker, MK. 2010. Cytochrome P4501A1 is Required for Vascular Dysfunction and Hypertension Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. Toxicol Sci. 117:537-546.
Kopf, PG, Walker, MK. 2010. 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Increases Reactive Oxygen Species Production in Human Endothelial Cells Via Induction of Cytochrome P4501A1. Toxicol Appl Pharmacol. 245:91-99.
Kopf, PG, Zhang, DX, Gauthier, KM, Nithipatikom, K, Yi, XY, Falck, JR, and Campbell, WB. 2010. Adrenic Acid Metabolites as Endogenous Endothelium- and Zona Glomerulosa-Derived Hyperpolarizing Factors. Hypertension. 55:547-554.
Kopf, PG, Huwe, JK, and Walker, MK. 2008. Subchronic 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice. Cardiovasc Toxicol. 8:181-193.
Aragon, AC, Kopf, PG, Campen, MJ, Huwe, JK, and Walker, MK. 2008. In Utero and Lactational 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure: Effects of Fetal and Adult Cardiac Gene Expression and Adult Cardiac and Renal Morphology. Toxicol Sci. 101:321-330.
Kopf, PG and Walker, MK. 2010. Mechanisms of Xenobiotic-Induced Cardiovascular Toxicology: Halogenated Aromatic Hydrocarbons and Cardiovascular Disease. Comprehensive Toxicology. Second Ed. Elsevier Limited, Oxford.
Kopf, PG and Walker, MK. 2009. Overview of Dioxin-Like Compounds, PCB, and Pesticide Exposures Associated with Developmental Heart Effects in Mammals, Fish, and Birds. J Env Sci Health, Part C. 27:276-285.