Showing papers by "Garret A. FitzGerald published in 2009"

Network Features of the Mammalian Circadian Clock

Abstract: The mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology in anticipation of daily environmental change. To assess the robustness of a human molecular clock, we systematically depleted known clock components and observed that circadian oscillations are maintained over a wide range of disruptions. We developed a novel strategy termed Gene Dosage Network Analysis (GDNA) in which small interfering RNA (siRNA)-induced dose-dependent changes in gene expression were used to build gene association networks consistent with known biochemical constraints. The use of multiple doses powered the analysis to uncover several novel network features of the circadian clock, including proportional responses and signal propagation through interacting genetic modules. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that these network features act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation.

COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice

Abstract: A cardinal feature of peripheral inflammation is pain. The most common way of managing inflammatory pain is to use nonsteroidal antiinflammatory agents (NSAIDs) that reduce prostanoid production, for example, selective inhibitors of COX2. Prostaglandins produced after induction of COX2 in immune cells in inflamed tissue contribute both to the inflammation itself and to pain hypersensitivity, acting on peripheral terminals of nociceptors. COX2 is also induced after peripheral inflammation in neurons in the CNS, where it aids in developing a central component of inflammatory pain hypersensitivity by increasing neuronal excitation and reducing inhibition. We engineered mice with conditional deletion of Cox2 in neurons and glial cells to determine the relative contribution of peripheral and central COX2 to inflammatory pain hypersensitivity. In these mice, basal nociceptive pain was unchanged, as was the extent of peripheral inflammation, inflammatory thermal pain hypersensitivity, and fever induced by lipopolysaccharide. By contrast, peripheral inflammation-induced COX2 expression in the spinal cord was reduced, and mechanical hypersensitivity after both peripheral soft tissue and periarticular inflammation was abolished. Mechanical pain is a major symptom of most inflammatory conditions, such as postoperative pain and arthritis, and induction of COX2 in neural cells in the CNS seems to contribute to this.

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function.

Abstract: Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the α-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.

Prostaglandin F2alpha elevates blood pressure and promotes atherosclerosis

Abstract: Little is known about prostaglandin F2α in cardiovascular homeostasis. Prostaglandin F2α dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus. Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory up-regulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs that exhibit mild polyuria and polydipsia. Atherogenesis is retarded by deletion of the FP, despite the absence of detectable receptor expression in aorta or in atherosclerotic lesions in Ldlr KOs. Although vascular TNFα, inducible nitric oxide enzyme and TGFβ are reduced and lesional macrophages are depleted in the FP/Ldlr double KOs, this result reflects the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine generation. Blockade of the FP offers an approach to the treatment of hypertension and its attendant systemic vascular disease.

Platelets, pyrexia, and plasmodia.

Abstract: Studies of mouse models indicate that an interaction between platelets and erythrocytes infected with plasmodia represses parasitemia but exacerbates cerebral infection.

Moving clinical research in academic medical centres up the value chain

Abstract: A decline in the approval of new molecular entities — particularly truly innovative ones — has coincided with an increasing emphasis on translational medicine by funders of the academic sector. How might the full potential of academic medical centres be realized?

A roadmap for the twilight zone: navigating United States cardiovascular career development for international trainees.

Abstract: Time is a one way street—except in the Twilight Zone! — —Rod Serling, host of the cult CBS television series Predictions of the demise of US preeminence in the sciences appear to have been exaggerated1; at least for now, objective measurements of the investment in and the impact of biomedical research in the United States suggest that it continues to dominate Europe, Japan, and China.2 The particular inequities of access to healthcare delivery in the United States are well documented,3,4 and objective measures of population health suggest that Americans, on average, are seriously disadvantaged, particularly compared with some Europeans.5 However, although a disproportionate investment of dollars in health care6 may not translate to universal benefit in the US system, it has created well-resourced centers of excellence that, if accessed, have the potential to deliver superior care.7 In the case of cardiology, these centers typically have well-established training programs that integrate diversified opportunities for specialized clinical training with access to mentors skilled in basic, translational, and clinical research. The comprehensive nature of these programs and their multiplicity remain unique to the United States and are sufficient reasons for every aspiring cardiologist or cardiovascular physician-scientist to consider seriously a period of training in this system. Every year, international trainees come to the United States to advance their careers in cardiovascular medicine. In 2006, international medical graduates (IMGs) from 127 countries filled 31% of accredited cardiovascular disease fellowship posts, 33% of clinical cardiac electrophysiology positions, and 46% of the interventional cardiology posts.8 In addition to clinical training, the potential for international trainees to perform cardiovascular research in the United States is considerable. Realizing the benefits of the training environment within the United States requires one to become familiar with institutional, state, and federal training requirements …

Abstract 5007: Variability in the Response to Aspirin

Abstract: Low dose aspirin is efficacious in the secondary prevention of stroke and myocardial infarction. It has been suggested that a syndrome of “aspirin resistance” constrains its efficacy. Despite this ...

ANTAGONISM OF PGF 2α RECEPTOR TO TREAT HYPERTENSION CHARACTERIZED BY ACTIVATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

Abstract: The present invention relates to methods for identifying candidate therapeutics for hypertension. The invention further provides a method for treating hypertension and/or decreasing atherogenesis by administration of an inhibitor of PGF2α receptor.

Neurofurans-indices of oxidant stress

Abstract: The invention is drawn to a new class of isoeicosanoids that have been identified as products of the oxidation of docosahexaenoic acid (DHA). The invention provides compositions and methods related to the new class of molecules.