Apoptosis, a form of programmed cell death, is a highly regulated mechanism involved in cellular homeostasis and organ remodeling. Although sustained inhibition of apoptosis can lead to uncontrolled cell proliferation (neoplasia), a pharmacologic approach that could prevent apoptotic cell death could have a profound beneficial impact in a variety of diseases associated with acute cellular injury. The mitochondria play a fundamental role in the two well-established molecular pathways controlling apoptosis by mediating release of cytochrome c into the cytosol This project will focus on inhibiting cytochrome c redox cycling induced oxidation of cardiolipin by the hemoprotein reductant acetaminophen. The goals of this project are to 1) investigate the mechanisms by which cytochrome c is released following cardiolipin oxidation in mitochondria and 2) establish the efficacy of acetaminophen to inhibit apoptosis in vivo at concentrations that are within the therapeutic range in humans, and 3) identify novel inhibitors of cytochrome c redox cycling as pharmacologic candidates for preventing apoptosis in vivo using an animal model of ischemia/reperfusion injury. These investigations will utilize a conjunction of methods including isolated mitochondria, cells in culture isolated from genetic variants, and various stimuli of apoptosis. The involvement of the two mitochondrial pores in these mechanisms will be tested as well as their relationship with oxidized cardiolipin. Finally, this project will assess the ability of acetaminophen to protect kidneys in vivo from ischemia/reperfusion injury induced apoptosis. Results in this proposal will provide preclinical data necessary for consideration of initial human trials in preventing apoptotic cell death associated with disorders such as myocardial infarction and stroke. Although acetaminophen is effective in inhibiting hemoprotein redox cycling induced lipid peroxidation, it is not the ideal drug for use in humans because of its associated propensity to cause hepatotoxicity, which prohibits dose escalation to enhance efficacy. In this regard, our studies will also evaluate novel synthetic compounds with the goal being to identify new potent inhibitors of cyt c redox cycling that have a high safety margin that could be further developed and eventually tested in humans.
Apoptosis, a form of programmed cell death, is involved in many diseases, including neurodegenerative diseases and ischemic injury following myocardial infarction and stroke. Currently, there are no therapeutic strategies available to directly inhibit the apoptotic process. Showing that acetaminophen can prevent apoptosis at normal human therapeutic concentrations will provide preclinical data necessary for consideration of initial human trials in preventing apoptotic cell death associated with these disorders.
|Simpson, Scott A; Zaccagni, Hayden; Bichell, David P et al. (2014) Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass. Pediatr Crit Care Med 15:503-10|
|Shonesy, Brian C; Bluett, Rebecca J; Ramikie, Teniel S et al. (2014) Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep 9:1644-53|
|Wu, Jing; Thabet, Salim R; Kirabo, Annet et al. (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616-25|
|Xu, Shu; Hermanson, Daniel J; Banerjee, Surajit et al. (2014) Oxicams bind in a novel mode to the cyclooxygenase active site via a two-water-mediated H-bonding Network. J Biol Chem 289:6799-808|
|Neau, David B; Bender, Gunes; Boeglin, William E et al. (2014) Crystal structure of a lipoxygenase in complex with substrate: the arachidonic acid-binding site of 8R-lipoxygenase. J Biol Chem 289:31905-13|
|Shuck, Sarah C; Wauchope, Orrette R; Rose, Kristie L et al. (2014) Protein modification by adenine propenal. Chem Res Toxicol 27:1732-42|
|Hermanson, Daniel J; Gamble-George, Joyonna C; Marnett, Lawrence J et al. (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358-67|
|Dikalov, Sergey I; Nazarewicz, Rafal R; Bikineyeva, Alfiya et al. (2014) Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal 20:281-94|
|Kirabo, Annet; Fontana, Vanessa; de Faria, Ana P C et al. (2014) DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest 124:4642-56|
|Trott, Daniel W; Thabet, Salim R; Kirabo, Annet et al. (2014) Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64:1108-15|
Showing the most recent 10 out of 31 publications