David P. Hajjar Professor of Pathology and Laboratory Medicine

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NITRIC OXIDE - EICOSANOID BIOCHEMISTRY

Atherosclerosis is an inflammatory disease characterized by the accretion of cholesterol-laden plaque in the artery wall. Progression of atherosclerosis results in injury to the structural integrity of a vessel, which may ultimately lead to thrombosis, stroke, and myocardial infarction. During the pathogenesis of atherosclerosis, alterations in eicosanoid biosynthesis and reactive oxygen species production occur by mechanisms that are not well understood. The delineation of these mechanisms is the focus of Dr. Hajjar's research.

Eicosanoids are a group of biologically active compounds derived from the cyclooxygenase (COX) and lipoxygenase catalytic pathways and include the commonly named prostaglandins. These eicosanoids play important physiological roles in the regulation of many processes; for example, thromboxane, a potent vasoconstrictor produced by platelets, is offset by prostacyclin, a potent vasodilator produced in the endothelium.

Nitric oxide (NO), produced in blood vessels by the nitric oxide synthases, is another critical mediator of both physiologic and pathophysiologic processes in the regulation of vascular tone and inflammation. Atherosclerotic lesions contain increased levels of inducible COX (COX-2) and nitric oxide synthase (iNOS). Furthermore, recent developments show that both enzymes are bound, and the fate of eicosanoid synthesis is linked to NO and its higher oxides (NOx) derived from iNOS. Given the complexity of NOx chemistry, ensuing studies on the effects of NOx on COX function have been controversial with reports of activation as well as inhibition, reflecting complex signaling "cross talk" involving nitric oxide metabolites and eicosanoids.

The principal aim of Dr. Hajjar's work is to define the mechanisms by which NO and prostaglandin synthetic pathways interact to alter eicosanoid biosynthesis as well as to investigate the impact of these mediators on atherosclerosis and thrombosis. Over the years, he has defined the roles and mechanisms of these complex signaling interactions in order to gain an understanding of the pathophysiological processes in atherosclerosis using animal models and the consequences of pharmacological interventions.

In recent work, he has showed that the enzyme prostaglandin H2 synthase (PGHS, also known as cyclooxygenase) regulates the production of eicosanoids that modulate physiologic processes in the vessel wall, contributing to atherosclerosis and thrombosis. Dr. Hajjar demonstrated that various forms of NOx can have different modulatory effects on the activity of PGHS-1, the predominant isozyme in platelets. These and other studies revealed that the active heme center of PGHS-1 regulates peroxynitrite-induced modification and loss of enzyme reactivity, indicating that heme may play a decisive role in catalyzing these processes in PGHS-1 when exposed to nitrative stress in an inflammatory setting.

Collectively, these studies show for the first time that iNOS influences PGHS expression and its activity, which can contribute to modification of an important enzyme involved in inflammation during atherosclerosis. Since iNOS-derived species are required for robust atherosclerosis-associated peroxynitrite production in peripheral organs, these studies have contributed importantly to our understanding of the complex alterations in eicosanoid metabolism that occur during the pathogenesis of heart disease where inflammation occurs.

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Primary Affiliation

  • Weill Cornell Medical College, Cornell University