This Program-Project Grant is to identify and define the cardiovascular effects of environmental aldehydes and pollutants that generate aldehydes. The project will integrate molecular and cellular aspects of aldehyde toxicity, delineate the contribution of individual pathways involved in the detoxification of the aldehydes, and elucidate how aldehydes affect atherosclerosis, platelet and endothelial activation, and myocardial function. Acrotein and trans-2-hexanal will be studied as model aldehydes most prevalent in the environment. The Program consists of 4 Projects and 3 Cores. Project 1: Aldehyde Metabolism and Cardiovascular Disease focuses on the metabolism of these toxicants in mice. These studies are designed to identify the major metabolic products and the biochemical pathways that metabolize aldehydes, and how glutathione S-transferases regulate this metabolism and cardiovascular toxicity. Project 2: Atherogenic Effects of Environmental Aldehydes will test the hypothesis that exposure to unsaturated aldehydes exacerbates atherogenesis. Spontaneously atherosclerotic apoE-null mice will be exposed to these pollutants, and changes in lesion progression and markers of vascular inflammation will be measured, and resultant alterations in plasma lipoproteins will be determined. The central hypothesis of Project 3: Role of Platelet Activation and Vascular Pathology in Aldehyde Toxicity is that environmental aldehydes activate blood cells and induce proinflammatory responses in the vascular endothelium. To test this hypothesis, we will examine platelet activation by aldehyde, investigate the role of platelet microparticle formation in aldehyde-induced vascular changes, and assess the ability of these aldehydes to stimulate platelet-lesion interactions. In Project 4: Acute and Chronic Cardiotoxicity of Aldehydes will examine how aldehydes acutely depress contractibility, exacerbate ischemic injury, and chronically induce inflammatory states contributing to remodeling characteristic of heart failure. For this, we will delineate the mechanisms by which aldehyde inflict contractile dysfunction, abolish ischemic preconditioning and induce pathological myocardial remodeling. The Administrative Core (A) will serve as the organizational focus and will provide infrastructure support, including statistical analysis, data management, coordinated sample handling and storage and sentinel monitoring for systemic toxicity. The Bioanalysis Core (B) will provide and integrated, centralized facility for biochemical determinations and mass spectrometry. The Inhalation Facility Core (C) will provide uniform acrolein exposures to mice via inhalation. Successful completion of this project will lead to a better understanding of the cardiovascular consequences of aldehyde exposure and will provide direction to future assessments of human risk and susceptibility.
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| DeJarnett, Natasha; Yeager, Ray; Conklin, Daniel J et al. (2015) Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133+ Circulating Angiogenic Cells. Arterioscler Thromb Vasc Biol 35:2468-77 |
| Kaiser, J Phillip; Guo, Luping; Beier, Juliane I et al. (2014) PKC? contributes to chronic ethanol-induced steatosis in mice but not inflammation and necrosis. Alcohol Clin Exp Res 38:801-9 |
| Makia, Ngome L; Surapureddi, Sailesh; Monostory, Katalin et al. (2014) Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and DNA looping. Mol Pharmacol 86:125-37 |
| DeJarnett, Natasha; Conklin, Daniel J; Riggs, Daniel W et al. (2014) Acrolein exposure is associated with increased cardiovascular disease risk. J Am Heart Assoc 3: |
| Salabei, Joshua K; Balakumaran, Arun; Frey, Justin C et al. (2012) Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy. Toxicol Appl Pharmacol 262:265-72 |
| Makia, N L; Amunom, I; Falkner, K C et al. (2012) Activator protein-1 regulation of murine aldehyde dehydrogenase 1a1. Mol Pharmacol 82:601-13 |
| Xie, Zhengzhi; Barski, Oleg A; Cai, Jian et al. (2011) Catalytic reduction of carbonyl groups in oxidized PAPC by Kv?2 (AKR6). Chem Biol Interact 191:255-60 |
| Conklin, Daniel J; Prough, Russell A; Juvan, Peter et al. (2011) Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase. Mol Nutr Food Res 55:1411-22 |
| Ismahil, Mohamed Ameen; Hamid, Tariq; Haberzettl, Petra et al. (2011) Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 301:H2050-60 |
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