The overall goal of this project is to understand the role of lipid peroxidation products in inducing cardiac injury and dysfunction caused by chronic hemodynamic stress. Our working hypothesis is that the effects of reactive oxygen species, generated in these hearts, are in part mediated by 4-hydroxyalkenals produced as a result of lipid peroxidation. We propose that modification of myocardial proteins by these aldehydes is a significant source of cardiac injury and dysfunction induced by chronic hemodynamic stress and therefore, metabolic detoxification of these aldehydes diminishes myocardial hypertrophy and heart failure. To test this hypothesis we will examine 4-hydroxyalkenal formation and metabolism in hearts subjected to transverse aortic constriction (TAC) and we will measure changes in the activity and the levels of aldehyde-metabolizing enzymes and cellular nucleophiles such as reduced glutathione and carnosine. To identify changes in aldehyde metabolism, metabolites of 4-hydroxy-trans-2-nonenal (HNE) generated in hypertrophic hearts perfused with radiolabeled HNE will be identified and quantified along with HNE metabolites generated in vivo in the blood and urine of mice subjected to TAC. To determine the role of aldehyde metabolism in regulating cardiac injury and dysfunction induced by pressure overload, we will examine whether genetic deletion of aldose reeducates (which catalyzes the reductive metabolism of aldehydes) or cardiospecific overexpression of carnosine synthase (which generates the aldehyde-quenching dipeptide - carnosine in the heart) affects myocardial injury and dysfunction after TAC. To examine the mechanism by which aldehydes induce myocardial injury, we will examine whether exposure to HNE triggers autophagy;whether the pathways of autophagy activated by HNE are also stimulated by TAC;and whether changes in aldehyde metabolism via aldose reductase and carnosine alter autophagic responses in hypertrophic and failing hearts. Completion of this project will lead to a better understanding of the role of oxidative stress in myocardial hypertrophy and heart failure as well as other chronic conditions associated with an increase in lipid peroxidation such as diabetes, atherosclerosis and cardiovascular aging. Our results could provide novel insights into the mechanisms by which hemodynamic stress induces myocardial injury and dysfunction and how these changes could be attenuated. We expect that these findings will have wide mechanistic, prognostic and therapeutic implications for diagnosis, management, and treatment of pathological hypertrophy and heart failure.

Public Health Relevance

Exposure to environmental aldehydes through either pollution or diet is a significant source of cardiac injury and dysfunction induced by chronic hemodynamic stress therefore determining how these aldehydes are removed from the system could lead to ways to reduce their effect. To test this hypothesis we will examine a specific aldehyde formation and metabolism in hearts subjected to reduced blood flow and we will measure changes in the activity and the levels of aldehyde-metabolizing enzymes and cellular nucleophiles in an effort to determine how to either block their damage or increase their metabolism to remove them prior to their causing injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-K (02))
Program Officer
Wang, Lan-Hsiang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Salabei, Joshua K; Lorkiewicz, Pawel K; Mehra, Parul et al. (2016) Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem 291:13634-48
Haberzettl, Petra; O'Toole, Timothy E; Bhatnagar, Aruni et al. (2016) Exposure to Fine Particulate Air Pollution Causes Vascular Insulin Resistance by Inducing Pulmonary Oxidative Stress. Environ Health Perspect 124:1830-1839
Conklin, Daniel J; Guo, Yiru; Jagatheesan, Ganapathy et al. (2015) Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury. Circ Res 117:437-49
Ma, Xiaodong; Conklin, Daniel J; Li, Fenge et al. (2015) The oncogenic microRNA miR-21 promotes regulated necrosis in mice. Nat Commun 6:7151
Weber, Susanne; Salabei, Joshua K; Möller, Gabriele et al. (2015) Aldo-keto Reductase 1B15 (AKR1B15): a mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates. J Biol Chem 290:6531-45
Singh, Mahavir; Kapoor, Aniruddh; Bhatnagar, Aruni (2015) Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls. Chem Biol Interact 234:261-73
Conklin, Daniel J; Haberzettl, Petra; Jagatheesan, Ganapathy et al. (2015) Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice. Toxicol Appl Pharmacol 285:136-48
Hellmann, Jason; Tang, Yunan; Zhang, Michael J et al. (2015) Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation. Prostaglandins Other Lipid Mediat 116-117:49-56
Salabei, Joshua K; Lorkiewicz, Pawel K; Holden, Candice R et al. (2015) Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. Stem Cells 33:2613-27
Sansbury, Brian E; Bhatnagar, Aruni; Hill, Bradford G (2014) Impact of nutrient excess and endothelial nitric oxide synthase on the plasma metabolite profile in mice. Front Physiol 5:453

Showing the most recent 10 out of 92 publications