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RESEARCH SUMMARY:
Our research focuses on discovering biochemical mechanisms that are responsible for the pathophysiological sequelae of cardiovascular diseases. The cardiovascular diseases that we study are coronary heart disease and atherosclerosis. Coronary heart disease and atherosclerosis are primary causes of heart attacks, stroke, and high blood pressure. Cardiovascular disease is the primary cause of death in the United States and the delineation of the biochemical mechanisms responsible for the initiation and the progression of cardiovascular diseases has been and remains an important public health concern in the United States and other industrialized nations. We have directed our efforts toward identifying biochemical mechanisms including the breakdown of membrane phospholipids, the alterations in fatty acid utilization, the activation of protein kinases, and the production of reactive oxygen species as key mechanisms involved in cardiovascular diseases.
We combine a diverse approach to studying biochemical events in the heart ranging from the utilization of basic physiological models of myocardial disease including coronary occlusion models, isolated perfused hearts, and isolated adult cardiac myocytes to the utilization of state-of-the-art instrumentation including GC-MS and ESI-MS analysis for small molecule discovery. Our studies have led to the discovery that plasma membrane and nuclear membrane phospholipids are targeted by phospholipases during myocardial ischemia (reduced blood flow to the heart) and reperfusion. In particular, we have shown that plasmalogen phospholipids are targeted by activated phospholipases during myocardial ischemia. With the recent discovery that nuclear phospholipids are targeted by phospholipases during ischemia, we have begun to focus on the possibility that the products of these phospholipases may serve as messengers in nuclear signaling pathways. Accordingly, we have discovered that these phospholipase products activate several protein kinases in the heart and mediate alter early gene products in the ischemic/reperfused heart. Next we would like to determine whether accelerated nuclear phospholipid catabolism is a signaling mechanism that leads to the synthesis of new proteins that may alter the performance of the heart following myocardial ischemia.
Myeloperoxidase (MPO) and MPO-derived products have been detected in human atherosclerotic lesions. We have recently demonstrated that MPO-derived, reactive chlorinating species (RCS) target the vinyl ether bond of tissue plasmalogens resulting in the production of the neutrophil chemoattractant, alpha-chloro-fatty aldehyde (alpha-Cl-FALD), and unsaturated molecular species of lysophosphatidylcholine (UnsatLPC). Furthermore, we have shown that alpha-Cl-FALD and UnsatLPC are present in human atherosclerotic lesions. In addition to alpha-Cl-FALD and UnsatLPC, current investigations are focusing on secondary products that may be derived from the attack of plasmalogens by RCS. The potential biological role of these RCS-derived plasmalogen catabolites is suggested by studies demonstrating that they are chemoattractants, cytotoxic, and alter gene transcription. These findings have led to the hypothesis that the targeting of tissue and lipoprotein plasmalogens by RCS is a biochemical mechanism responsible for the generation of a novel family of lipidic mediators of atherosclerosis. This hypothesis is currently being tested through experiments that are identifying the RCS-derived plasmalogen catabolites in human atherosclerotic lesions and in tissues targeted by activated phagocytes as well as studies that aredirected at demonstrating that plasmalogen attack by RCS is an important biochemical mechanism that produces lipidic mediators that propagate atherosclerosis.
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