The studies of the Cyp2c epoxygenase and Cyp4a omega-hydroxylase branches of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase pathway have uncovered important functional roles for these enzymes in cell and organ physiology. Thus, the epoxy- and hydroxy-AA products of these enzymes (EETs and 20-HETE, respectively) participate in the regulation of renal transport and hemodynamics and thus, in the control and plasma salt and volume homeostasis. Mouse models of Cyp2c44 and Cyp4a10 dysfunction show a type of hypertension that is, as with prevalent forms of the human disease, sensitive to dietary salt intake, and linked to alterations in sodium transport. Genetic studies have uncovered associations between a variant of the human CYP4A11 gene and hypertension, and suggested a role for this 20-HETE synthase in the pathophysiology of salt sensitive hypertension. However, the site and mode of action of the P450 metabolites remains to be unequivocally defined, as it is their relevance to human hypertension and renal disease. Project #1, in conjunction with the functional components of the Program Project, will utilize molecular approaches for the characterization of mouse models of P450 isoform-dependent function and/or dysfunction, and for studies of the mechanisms of action their metabolites. Gene disruption and/or overexpression will be applied to studies of the physiological and/or pathophysiological role(s) of the Cyp2c44 epoxygenase and Cyp4a12 omega-hydroxylase. In collaborafion with Projects 2-5, we will use combinations of funcfional and biochemical approaches for: a) the analysis of P45b gene-dependent changes in AA metabolism and P450 isoform organ expression and regulation, and b) studies of the relevance of their human homologues to the pathophysiology of hypertension and renal disease. Our long term goals are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answers to these important quesfions are needed for the unequivocal definition of the physiological significance of these enzymes, their roles in human diseases such as hypertension, and for the development of rational strategies for future pharmacological and/or clinical intervention.
Accumulafing genetic and funcfional evidence points to a AA monooxygenase role in the pathophysiology of hypertension and renal disease. The identification of the role and mechanism of action of these enzymes and their products is of vital importance for the development of new diagnostic tools and therapeutic approaches for the management of hypertension, and to prevent its devastating chronic consequences.
|Elijovich, Fernando; Milne, Ginger L; Brown, Nancy J et al. (2018) Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects. Hypertension 71:346-355|
|Sausville, Lindsay N; Gangadhariah, Mahesha H; Chiusa, Manuel et al. (2018) The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer Res 78:4865-4877|
|Garcia, Victor; Gilani, Ankit; Shkolnik, Brian et al. (2017) 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res 120:1776-1788|
|Guo, Zhijun; Sevrioukova, Irina F; Denisov, Ilia G et al. (2017) Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chem Biol 24:1259-1275.e6|
|Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286|
|Gangadhariah, Mahesha H; Dieckmann, Blake W; Lantier, Louise et al. (2017) Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia 60:1066-1075|
|Shuey, Megan M; Billings 4th, Frederic T; Wei, Shouzou et al. (2017) Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery. PLoS One 12:e0175292|
|Fan, Fan; Pabbidi, Mallikarjuna R; Ge, Ying et al. (2017) Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am J Physiol Renal Physiol 312:F971-F981|
|Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65|
|Chiba, Takuto; Skrypnyk, Nataliya I; Skvarca, Lauren Brilli et al. (2016) Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. J Am Soc Nephrol 27:495-508|
Showing the most recent 10 out of 376 publications