Coronary heart disease is responsible for the sudden death of over 500,000 U.S. citizens per year. The patho- physiological sequelae following myocardial ischemia include depressed myocardial function leading to con- gestive heart failure and death. Following ischemia, neutrophils both interact with endothelium and infiltrate in- jured myocardium. Activated neutrophils produce HOCl that can target the biomolecules present in the heart leading to further injury and the generation of chlorinated products. We discovered that the vinyl ether bond of plasmalogens is a preferred target of neutrophil-derived HOCl, resulting in the production of 2- chlorohexadecanal and several other chlorinated lipids. Plasmalogens are a predominant phospholipid subclass in tissues of the cardiovascular system. Based on the discovery that activated neutrophils initiate the accumulation of a family of chlorinated lipids and our preliminary data indicating that chlorinated lipids decrease cardiac work, the overall goal of this proposal is to test the hypothesis that novel chlorinated lipids and their metabolites are mediators of post-ischemic dysfunction. This hypothesis will be tested by two specific aims. The goals of Specific Aim 1 are to examine the diverse family of chlorinated lipids that are produced in vivo during myocardial ischemia/reperfusion (I/R). Alterations in the accumulation of myocardial chlorinated lipids in response to I/R will be examined in reversibly and irreversibly injured hearts from neutropenic and normal rats. Chlorinated lipid metabolites in the plasma and urine will also be assessed to examine their potential role as biomarkers of cardiac injury. Results from Aim 1 will establish physiologically relevant levels of chlorinated lipids that will be applied to ex vivo working hearts in Aim 2. The goals of Specific Aim 2 are to demonstrate that physiologically relevant concentrations of chlorinated lipids and their metabolites elicit cardiac contractile dysfunction. Isolated working rat hearts will be treated with stable isotope-labeled chlorinated lipids to test their role as modulators of cardiac contractile function, as well as their metabolism using a novel mass spectrometric screening assay that exploits both stable isotope and monochlorinated molecular signatures of the metabolites. The proposed studies are innovative because they will delineate new mediators of post- ischemic contractile dysfunction and will potentially identify chlorinated lipid metabolites as new biomarker candidates of cardiac injury. Understanding the biochemical mechanisms responsible for depressed cardiac function following myocardial ischemia represents a major U.S. health concern. Identifying new mediators that impact post-ischemic function may lead to improved insights for patient care in the future. Since this is an R21 application based on the """"""""high risk"""""""", innovative and exploratory nature of this proposal, we will focus on identifying the family of chlorinated lipid metabolites produced during myocardial I/R, and identify their impact on contractile dysfunction. Putative mechanisms by which these chlorinated lipid metabolites elicit contractile dysfunction are discussed as future studies stemming from this exploratory study.
Elucidating the mechanisms that chlorinated lipids mediate the pathophysiological sequelae of myocardial ischemia/reperfusion is important from a U.S. public health perspective. We have discovered a new family of chlorinated lipids that are produced as a result of neutrophil activation. The role of these chlorinated lipids in post-ischemic contractile dysfunction will be examined in the proposed studies.
|Aroor, Annayya R; Habibi, Javad; Ford, David A et al. (2015) Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function. Diabetes 64:1988-2001|
|Soufi, Nisreen; Hall, Angela M; Chen, Zhouji et al. (2014) Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice. J Biol Chem 289:30177-88|
|Baldan, Angel; Gonen, Ayelet; Choung, Christina et al. (2014) ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis. J Immunol 193:5637-48|
|Yang, Yanbo; Kuwano, Takashi; Lagor, William R et al. (2014) Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species. Lipids 49:505-15|
|Wang, Wen-yi; Albert, Carolyn J; Ford, David A (2014) Alpha-chlorofatty acid accumulates in activated monocytes and causes apoptosis through reactive oxygen species production and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol 34:526-32|
|Shao, Fei; Ford, David A (2014) Elaidic acid increases hepatic lipogenesis by mediating sterol regulatory element binding protein-1c activity in HuH-7 cells. Lipids 49:403-13|
|Wang, Wen-Yi; Albert, Carolyn J; Ford, David A (2013) Approaches for the analysis of chlorinated lipids. Anal Biochem 443:148-52|
|Shao, Fei; Ford, David A (2013) Differential regulation of ABCA1 and macrophage cholesterol efflux by elaidic and oleic acids. Lipids 48:757-67|
|Rong, Xin; Albert, Carolyn J; Hong, Cynthia et al. (2013) LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab 18:685-97|
|Balogun, Kayode A; Albert, Carolyn J; Ford, David A et al. (2013) Dietary omega-3 polyunsaturated fatty acids alter the fatty acid composition of hepatic and plasma bioactive lipids in C57BL/6 mice: a lipidomic approach. PLoS One 8:e82399|
Showing the most recent 10 out of 16 publications