Showing papers by "Garret A. FitzGerald published in 2004"

BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis

Abstract: Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

Coxibs and Cardiovascular Disease

Abstract: The coxibs are a subclass of nonsteroidal antiinflammatory drugs (NSAIDs) designed to inhibit selectively cyclooxygenase-2 (COX-2).1 Their development was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and that cyclooxygenase-1 (COX-1) was the source of the same prostaglandins in gastric epithelium, where they afford cytoprotection. Three coxibs — celecoxib, rofecoxib, and valdecoxib — have been approved for use by the Food and Drug Administration (FDA); a fourth, etoricoxib, has been approved by the European regulatory authority, and it and a fifth, lumiracoxib, are currently under consideration for FDA . . .

COX-2-Derived Prostacyclin Confers Atheroprotection on Female Mice

Abstract: Female gender affords relative protection from cardiovascular disease until the menopause. We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin, PGI2, by activation of cyclooxygenase 2 (COX-2). This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the PGI2 receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. This suggests that chronic treatment of patients with selective inhibitors of COX-2 could undermine protection from cardiovascular disease in premenopausal females.

Directed Vascular Expression of Human Cysteinyl Leukotriene 2 Receptor Modulates Endothelial Permeability and Systemic Blood Pressure

Abstract: Background— The proinflammatory and vascular actions of cysteinyl leukotrienes (CysLTs) are mediated by 2 receptors: cysteinyl leukotriene 1 receptor (CysLT1R) and cysteinyl leukotriene 2 receptor (CysLT2R). However, the distinct contribution of CysLT2R to the vascular actions of CysLTs has not been addressed. Methods and Results— We generated an endothelial cell–specific human CysLT2R (EC-hCysLT2R) transgenic (TG) mouse model using the Tie2 promoter/enhancer. Strong expression of hCysLT2R in TG lung and endothelial cells, detected by real-time polymerase chain reaction, markedly enhanced CysLT-stimulated intracellular calcium mobilization compared with endogenous expression in cells from nontransgenic mice. The permeability response to exogenous LTC4 and to endogenous CysLTs evoked by passive cutaneous anaphylaxis was augmented in TG mice. The rapid, systemic pressor response to intravenous LTC4 was also diminished in TG mice coincidentally with augmented production of nitric oxide. Conclusions— The deve...

Terms and Conditions Semantic Complexity and Aspirin Resistance

Abstract: The term aspirin resistance has been used to describe the occurrence of cardiovascular events despite regular aspirin intake at recommended doses.1 In this context, such treatment failures resemble those with any drugs, including statins, -blockers, and ACE inhibitors.2,3 In secondary prevention, the clinical effectiveness of aspirin has been clearly demonstrated and is comparable to that of these other agents in that they all reduce nonfatal cardiovascular disease events by 25% to 30% and fatal events by 15% to 20% in randomized trials.3 These results represent a small to moderate but clinically worthwhile reduction in risk. Conversely, they suggest that 70% to 75% of nonfatal and 80% to 85% of fatal events are not prevented by these drugs. Mechanistic approaches to investigating aspirin resistance have relied heavily on ex vivo evaluations of platelet function. Although thrombosis is the proximate cause of virtually all occlusive vascular events,4 other factors, such as vascular function,5 and perhaps interactions with other blood cells, such as monocytes,6 are also probably relevant. It is unknown precisely how the impact of aspirin on the ex vivo response to selected concentrations of single aggregating agonists might model its efficacy in preventing clinical events in vivo. Multiple factors may confound platelet aggregometry, including posture, time of day, smoking, exercise, and blood cholesterol.7–9 Indeed, platelet aggregability may recover despite sustained inhibition of thromboxane during chronic dosing with aspirin.10 The term aspirin resistance is insufficiently precise to offer a credible basis for clinical decision making. More usefully, the multiple potential causes of treatment failure on aspirin might be pursued and named accordingly.11 Aspirin irreversibly acetylates a serine residue at position 530 on the cyclooxygenase (COX) enzyme, thus inhibiting the first step in the transformation of arachidonic acid to the platelet agonist thromboxane A2. The irreversible nature of COX inhibition underlies the ability of low doses of aspirin administered chronically to inhibit platelet aggregation in vivo.13 There is a nonlinear relationship of inhibition of platelet thromboxane A2 generation with inhibition of thromboxane-mediated platelet aggregation, requiring in excess of 95% inhibition to influence function.14 Although inhibition of platelet COX-1 at low aspirin doses is sufficient to explain the benefits on cardiovascular disease consistently observed in randomized trials, direct comparisons of clinical efficacy with higher aspirin doses, in which other mechanisms may be operative,15 have not been performed. Aspirin resistance has relied primarily on quantitative interpretations of the impact of aspirin on platelet aggregation ex vivo,16 occasionally on serum thromboxane B2, and in one instance on urinary 11-dehydrothromboxane B2 excretion.18 Although all of these approaches have been useful in exploring the clinical pharmacology of aspirin, none of them have been related quantitatively to clinical outcomes in individuals. Thus, the inference that a quantitative response in one of these variables to aspirin administration might predict the efficacy of aspirin in preventing a heart attack or stroke in that individual is presently unsubstantiated. Furthermore, chance, bias, and/or confounding are plausible alternative explanations for the findings from all of these studies. These limitations include technical reproducibility, adequate blinding of the investigators, assurance of compliance, and controls for recognized modifiers of the aggregation response mentioned above. Thus, it would seem premature and unwarranted to suggest that measurement of aggregation or thromboxane generation after dosing with aspirin could be used to categorize patients as “resistant” or “responsive” to aspirin in a way that reliably predicted clinical outcome and guided therapeutic decision making. Aside from aspects of trial design and technical limitations, it is quite possible that distinct molecular mechanisms may indeed contribute to treatment failure with aspirin. These include genetic variability in the target cyclooxygenases19 or indeed in proteins relevant to aspirin disposition. Although cyclooxygenase polymorphisms have been described,20 they have yet to be related to clinical outcome. One plausible explanation for the occurrence of an event despite aspirin intake may relate to drug–drug interactions. For example, nonsteroidal antiinflammatory drugs may interact pharmacodynamically with aspirin, compromising its ability to sustain inhibition of platelet thromboxane formation.21

Antimitogenic effects of HDL and APOE mediated by Cox-2–dependent IP activation

Abstract: HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor‐binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein‐dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP. Indeed, we found that HDL and APOE suppress aortic smooth muscle cell cycle progression by stimulating Cox-2 expression, leading to prostacyclin synthesis and an IP-dependent inhibition of the cyclin A gene. Similar results were detected in human aortic smooth muscle cells and in vivo using mice overexpressing APOE. Our results identify the Cox-2 gene as a target of APOE signaling, link HDL and APOE to IP action, and describe a potential new basis for the cardioprotective effect of HDL and APOE.

Signaling through the Prostaglandin I2 Receptor IP Protects against Respiratory Syncytial Virus-Induced Illness

Abstract: The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I 2 (PGI 2 ). Mice that overexpress PGI 2 synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI 2 receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI 2 is a potential therapeutic target in the treatment of RSV.

Prostaglandin E Synthases in Zebrafish

Abstract: Objective— Prostaglandin E synthases (PGESs) are being explored as antiinflammtory drug targets as alternatives to cyclooxygenase (COX)-2. Located downstream of the cyclooxygenases, PGESs catalyze PGE2 formation, and deletion of microsomal (m)-PGES-1 abrogates inflammation. We sought to characterize the developmental expression of COX and PGES in zebrafish. Methods and Results— We cloned zebrafish cytosolic (c) and m-PGES orthologs and mapped them to syntenic regions of chromosomes 23 and 5. cPGES was widely expressed during development and was coordinately regulated with zCOX-1 in the inner ear, the pronephros, and intestine. COX-2 and mPGES-1 exhibited restricted expression, dominantly in the vasculature of the aortic arch. However, the enzymes were anatomically segregated within the vessel wall. Experiments with antisense morpholinos and with nonsteroidal antiinflammatory drugs suggest that these genes may not be critical for development. Conclusions— mPGES-1 is developmentally coregulated with COX-2 in vasculature. Given the high fecundidity and translucency of the zebrafish, this model may afford a high throughput system for characterization of novel PGES inhibitors.

Prostaglandins: modulators of inflammation and cardiovascular risk.

Abstract: Cyclooxygenase (COX)-2-specific drugs such as rofecoxib and celecoxib and the newer agents, etoricoxib and valdecoxib, were developed to provide a safer alternative to traditional nonsteroidal antiinflammatory drugs (tNSAIDs). These drugs have been shown significantly to reduce endoscopically visualized gastrointestinal ulcers, and one of them, rofecoxib, has demonstrated a 50% reduction in clinically important gastrointestinal outcomes compared with a tNSAID. However, COX-derived prostaglandins also have complex interactions with the cardiovascular system. This article briefly reviews our current understanding of the interactions between prostaglandins and cardiovascular physiology, and addresses some of the concerns that recently have been raised regarding coxibs and the risk of cardiovascular events.