Showing papers by "Garret A. FitzGerald published in 2006"

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Abstract: We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2-derived prostacyclin (PGI(2)) and PGE(2). Therefore, the challenge remains to identify a mechanism whereby PGI(2) and PGE(2) expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2-derived PGI(2), was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE(2) biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE(2) expression, augmented PGI(2) expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their antiinflammatory efficacy by depressing PGE(2), while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI(2) suppression.

Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis

Abstract: Prostaglandin (PG) E2 is formed from PGH2 by a series of PGE synthase (PGES) enzymes. Microsomal PGES-1−/− (mPGES-1−/−) mice were crossed into low-density lipoprotein receptor knockout (LDLR−/−) mice to generate mPGES-1−/− LDLR−/−s. Urinary 11α-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M) was depressed by mPGES-1 deletion. Vascular mPGES-1 was augmented during atherogenesis in LDLR−/−s. Deletion of mPGES-1 reduced plaque burden in fat-fed LDLR−/−s but did not alter blood pressure. mPGES-1−/− LDLR−/− plaques were enriched with fibrillar collagens relative to LDLR−/−, which also contained small and intermediate-sized collagens. Macrophage foam cells were depleted in mPGES-1−/− LDLR−/− lesions, whereas the total areas rich in vascular smooth muscle cell (VSMC) and matrix were unaltered. mPGES-1 deletion augmented expression of both prostacyclin (PGI2) and thromboxane (Tx) synthases in endothelial cells, and VSMCs expressing PGI synthase were enriched in mPGES-1−/− LDLR−/− lesions. Stimulation of mPGES-1−/− VSMC and macrophages with bacterial LPS increased PGI2 and thromboxane A2 to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF1α, but not 2,3-dinor-TxB2, was increased in mPGES-1−/− LDLR−/−s. mPGES-1-derived PGE2 accelerates atherogenesis in LDLR−/− mice. Disruption of this enzyme retards atherogenesis, without an attendant impact on blood pressure. This may reflect, in part, rediversion of accumulated PGH2 to augment formation of PGI2. Inhibitors of mPGES-1 may be less likely than those selective for cyclooxygenase 2 to result in cardiovascular complications because of a divergent impact on the biosynthesis of PGI2.

COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis.

Abstract: Prostacyclin is one of a number of lipid mediators elaborated from the metabolism of arachidonic acid by the cyclooxygenase (COX) enzymes. This prostanoid is a potent inhibitor of platelet aggregat...

Role of Prostacyclin versus Peroxisome Proliferator-Activated Receptor β Receptors in Prostacyclin Sensing by Lung Fibroblasts

Abstract: Prostacyclin and its mimetics are used therapeutically for the treatment of pulmonary hypertension. These drugs act via cell surface prostacyclin receptors (IP receptors); however, some of them can also activate the nuclear receptor peroxisome proliferator-activated receptor beta (PPARbeta). We examined the possibility that PPARbeta is a therapeutic target for the treatment of pulmonary hypertension. Using the newly approved (for pulmonary hypertension) prostacyclin mimetic treprostinil sodium, reporter gene assays for PPARbeta activation and measurement of lung fibroblast proliferation were analyzed. Treprostinil sodium was found to activate PPARbeta in reporter gene assays and to inhibit proliferation of human lung fibroblasts at concentrations consistent with an effect on PPARs but not on IP receptors. The effects of treprostinil sodium on human lung cell proliferation are mimicked by those of the highly selective PPARbeta ligand GW0742. There are no receptor antagonists for PPARbeta or for IP receptors, but by using lung fibroblasts cultured from mice lacking PPARbeta (PPARbeta-/-) or IP (IP-/-), we demonstrate that the antiproliferative effects of treprostinil sodium are mediated by PPARbeta and not IP in lung fibroblasts. These observations suggest that some of the local, longer-term benefits of treprostinil sodium on reducing the remodeling associated with pulmonary hypertension may be mediated by PPARbeta. This study is the first to identify PPARbeta as a potential therapeutic target for the treatment of pulmonary hypertension, which is important because orally active PPARbeta ligands have been developed for the treatment of dyslipidemia.

Genetic model of selective COX2 inhibition reveals novel heterodimer signaling.

Abstract: Selective inhibitors of cyclooxygenase-2 (COX2) have attracted widespread media attention because of evidence of an elevated risk of cardiovascular complications in placebo-controlled trials, resulting in the market withdrawal of some members of this class. These drugs block the cyclooxygenase activity of prostaglandin H synthase-2 (PGHS2), but do not affect the associated peroxidase function. They were developed with the rationale of conserving the anti-inflammatory and analgesic actions of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) while sparing the ability of PGHS1-derived prostaglandins to afford gastric cytoprotection. PGHS1 and PGHS2 coexist in the vasculature and in macrophages, and are upregulated together in inflammatory tissues such as rheumatoid synovia and atherosclerotic plaque. They are each believed to function as homodimers. Here, we developed a new genetic mouse model of selective COX2 inhibition using a gene-targeted point mutation, resulting in a Y385F substitution. Structural modeling and biochemical assays showed the ability of PGHS1 and PGHS2 to heterodimerize and form prostaglandins. The heterodimerization of PGHS1-PGHS2 may explain how the ductus arteriosus closes normally at birth in mice expressing PGHS2 Y385F, but not in PGHS2-null mice.

Central and peripheral clocks in cardiovascular and metabolic function.

Abstract: The molecular circadian clock entrains biological rhythms to a 24-hour schedule Aspects of cardiovascular physiology and, indeed, the incidence of myocardial infarction and stroke are also subject to diurnal variation The use of rodent models of disrupted clock function has begun to elucidate the role of the molecular clock in the pathophysiology of cardiovascular and metabolic disease

Eicosanoids and the vascular endothelium.

Abstract: Cyclooxygenase (COX) enzymes catalyse the biotransformation of arachidonic acid to prostaglandins which subserve important functions in cardiovascular homeostasis. Prostacyclin (PGI2) and prostaglandin (PG)E2, dominant products of COX activity in macroand microvascular endothelial cells, respectively, in vitro, modulate the interaction of blood cells with the vasculature and contribute to the regulation of blood pressure. COXs are the target for inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs—which include those selective for COX-2) and for aspirin. Modulation of the interaction between COX products of the vasculature and platelets underlies both the cardioprotection afforded by aspirin and the cardiovascular hazard which characterises specific inhibitors of COX-2.

Biomarkers of Oxidant Stress in Vivo: Oxidative Modifications of Lipids, Proteins and DNA

Abstract: Oxidative stress (OS) has been widely implicated in physiological processes, such as aging and in disease pathogenesis, ranging from carcinogenesis through the aetiology of Alzheimer's disease to atherogenesis. However, until recently our ability to interrogate integrated systems, such as model organisms and humans, has been restricted by the lack of availability of quantitiative indices of oxidant stress in vivo. Indeed, the failure to identify benefit from antioxidants in clinical trials thus far may reflect, in part, the absence of such biomarkers to identify susceptible patients and to guide drug response^ ' \ This review focuses on developments in the analytical biochemistry of oxidant stress. Particular emphasis is placed on the still emerging technologies to study oxidative damage to DNA in vivo. The emergence of these new technologies promises to elucidate the role of this process in human disease and to afford a necessary adjunct to the development of novel antioxidant therapeutic strategies^^l