Since plasmalogens are the predominant phospholipid constituents of sarcolemma and are selectively hydrolyzed during myocardial ischemia, the goal of the proposed studies is the demonstration that accelerated plasmalogen catabolism is a biochemical mediator of the pathophysiologic sequelae of myocardial ischemia.The identification of accelerated plasmalogen catabolism in the sarcolemmal compartment of Intact ischemic hearts will be achieved by electron microscopic autoradiography employing maximum-likelihood analysis. To discriminate between phospholipase C- and D- mediated plasmalogen polar head group turnover, electrospray mass spectrometry(a divisional resource)will be exploited to quantitate 18/O- labeled phosphocholine and 18/O-labeled phosphatidic acid produced by H2 18/O-labeled cardiac myocytes. Electrophysiologic dysfunction mediated by accelerated plasmalogen polar head group turnover will be assessed in voltage-clamped Sf9 cells (containing overexpressed K+ channels) and neonatal cardiac myocytes that overexpress enzymes catalyzing polar head group remodeling. The effects of calcium-independent PLA2 on electrophysiologic function will be assessed utilizing patch-clamped myocytes perfused with purified calcium-Independent PLA2 in the presence and absence of the specific mechanism-based inhibitor of calcium- independent PLA2 (HELSS). The physiologic role of accelerated plasmalogen catabolism also will be assessed by characterizing protein kinases that are activated by plasmalogen catabolites during ischemia. The scientific environment and resources at Washington University provide a unique opportunity to execute the proposed studies. Taken together, a RCDA would provide support for a multidisciplinary, state-of-the-art approach to directly demonstrate the importance of accelerated plasmalogen catabolism in mediating the pathophysiologic sequelae of myocardial ischemia. Furthermore, a RCDA would provide critical support at this Important juncture in my research career which will facilitate my career goals of identifying the importance of alterations in phospholipid structure and function in mediating cardiovascular dysfunction in clinically relevant disease states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
1K04HL003316-01
Application #
2211525
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1995-04-10
Project End
1996-01-31
Budget Start
1995-04-10
Budget End
1996-01-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ford, David A (2002) Alterations in myocardial lipid metabolism during myocardial ischemia and reperfusion. Prog Lipid Res 41:6-26
Albert, C J; Crowley, J R; Hsu, F F et al. (2001) Reactive chlorinating species produced by myeloperoxidase target the vinyl ether bond of plasmalogens: identification of 2-chlorohexadecanal. J Biol Chem 276:23733-41
Williams, S D; Ford, D A (2001) Calcium-independent phospholipase A(2) mediates CREB phosphorylation and c-fos expression during ischemia. Am J Physiol Heart Circ Physiol 281:H168-76
Marshall, J; Krump, E; Lindsay, T et al. (2000) Involvement of cytosolic phospholipase A2 and secretory phospholipase A2 in arachidonic acid release from human neutrophils. J Immunol 164:2084-91
Williams, S D; Hsu, F F; Ford, D A (2000) Electrospray ionization mass spectrometry analyses of nuclear membrane phospholipid loss after reperfusion of ischemic myocardium. J Lipid Res 41:1585-95
Albert, C J; Ford, D A (1999) Protein kinase C translocation and PKC-dependent protein phosphorylation during myocardial ischemia. Am J Physiol 276:H642-50
Albert, C J; Ford, D A (1998) Identification of specific nuclear protein kinase C isozymes and accelerated protein kinase C-dependent nuclear protein phosphorylation during myocardial ischemia. FEBS Lett 438:32-6
Hale, C C; Ebeling, E G; Hsu, F F et al. (1998) The selective activation of the cardiac sarcolemmal sodium-calcium exchanger by plasmalogenic phosphatidic acid produced by phospholipase D. FEBS Lett 422:247-51
Williams, S D; Ford, D A (1997) Activation of myocardial cAMP-dependent protein kinase by lysoplasmenylcholine. FEBS Lett 420:33-8
Ford, D A; Hale, C C (1996) Plasmalogen and anionic phospholipid dependence of the cardiac sarcolemmal sodium-calcium exchanger. FEBS Lett 394:99-102

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