Papers by Joseph Loscalzo
Circulation, 2012
Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropi... more Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli.
S alicylates, in the form of willow bark, were used as an analgesic during the time of Hippocrate... more S alicylates, in the form of willow bark, were used as an analgesic during the time of Hippocrates, and their antipyretic effects have been recognized for more than 200 years. 1 Acetylsalicylic acid, or aspirin, was introduced in the late 1890s 2 and has been used to treat a variety of inflammatory conditions; however, the antiplatelet activity of this agent was not recognized until almost 70 years later. 3 Recent advances in our understanding of the central role of platelets in the pathophysiology of cardiovascular disease have spurred in-depth investigations into the mechanisms of action of aspirin and the clinical utility of this agent in the treatment of common cardiovascular disorders.
Journal of The American College of Cardiology, 1996
New England Journal of Medicine, 2009
Cell metabolism, Jan 5, 2015
The altered metabolism of tumor cells confers a selective advantage for survival and proliferatio... more The altered metabolism of tumor cells confers a selective advantage for survival and proliferation, and studies have shown that targeting such metabolic shifts may be a useful therapeutic strategy. We developed an intensely fluorescent, rapidly responsive, pH-resistant, genetically encoded sensor of wide dynamic range, denoted SoNar, for tracking cytosolic NAD(+) and NADH redox states in living cells and in vivo. SoNar responds to subtle perturbations of various pathways of energy metabolism in real time, and allowed high-throughput screening for new agents targeting tumor metabolism. Among > 5,500 unique compounds, we identified KP372-1 as a potent NQO1-mediated redox cycling agent that produced extreme oxidative stress, selectively induced cancer cell apoptosis, and effectively decreased tumor growth in vivo. This study demonstrates that genetically encoded sensor-based metabolic screening could serve as a valuable approach for drug discovery.
Circulation, Jan 31, 2015
Science (New York, N.Y.), Jan 20, 2015
According to the disease module hypothesis, the cellular components associated with a disease seg... more According to the disease module hypothesis, the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data have sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant coexpression patterns, symptom similarity, and comorbidity, whereas diseases residing in separated network neighborhoods are phenotypically distinct. These tools represent an interactome-based platform to predict molecular commonalities between phenotypically related diseases, even if ...
Pulmonary circulation, 2014
Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes ... more Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes of epigenetic regulation exist: DNA methylation, histone modification, and noncoding RNA action. In the cardiovascular system, epigenetic regulation affects development, differentiation, and disease propensity or expression. Defining the determinants of epigenetic regulation offers opportunities for novel strategies for disease prevention and treatment.
Wiley interdisciplinary reviews. Systems biology and medicine
Contemporary views of human disease are based on simple correlation between clinical syndromes an... more Contemporary views of human disease are based on simple correlation between clinical syndromes and pathological analysis dating from the late 19th century. Although this approach to disease diagnosis, prognosis, and treatment has served the medical establishment and society well for many years, it has serious shortcomings for the modern era of the genomic medicine that stem from its reliance on reductionist principles of experimentation and analysis. Quantitative, holistic systems biology applied to human disease offers a unique approach for diagnosing established disease, defining disease predilection, and developing individualized (personalized) treatment strategies that can take full advantage of modern molecular pathobiology and the comprehensive data sets that are rapidly becoming available for populations and individuals. In this way, systems pathobiology offers the promise of redefining our approach to disease and the field of medicine.
Current atherosclerosis reports, 2007
Numerous retrospective and prospective observational studies support an association between eleva... more Numerous retrospective and prospective observational studies support an association between elevated homocysteine and increased risk for myocardial infarction, stroke, and peripheral vascular disease. Although folic acid therapy substantially reduces homocysteine levels, recent large, randomized controlled trials failed to translate folic acid-induced homocysteine reduction into clinical benefit for the secondary prevention of cardiovascular events. These studies are compelling and have generated some newfound skepticism regarding a clinical role for folic acid therapy. Because these intervention trials have been limited to patients with mild hyperhomocysteinemia, the results of the trials imply that folic acid therapy may be best suited for individuals with more robustly elevated homocysteine levels. Furthermore, the potential benefit of folic acid therapy for primary prevention in individuals at low- or intermediate-risk for atherothrombotic disease has not been studied to date. T...
Current atherosclerosis reports, 2003
Hyperhomocysteinemia has long been recognized as a risk factor for cardiovascular disease. Many c... more Hyperhomocysteinemia has long been recognized as a risk factor for cardiovascular disease. Many cross-sectional and retrospective case-control studies have shown an association between elevated total homocysteine levels and coronary, peripheral, and cerebral vascular disease; prospective studies, however, have been inconsistent. Overall, there is evidence to suggest a modest association between elevated homocysteine levels and cardiovascular disease risk. Folate supplementation has been shown to reduce plasma homocysteine even when levels are in the normal range. Clinical studies suggest that lowering plasma homocysteine may improve endothelial dysfunction, a marker of atherothrombotic risk. The long-term effects of folate supplementation on homocysteine levels and cardiovascular disease risk await the results of ongoing clinical trials. However, several recent studies suggest a benefit for reduction of plasma homocysteine levels, as individuals with lower homocysteine have reduced ...
Nature, Jan 12, 1993
Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this app... more Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its in...
Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation ... more Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia and profoundly influences cell survival and function; however, the underlying molecular mechanisms are incompletely understood. Primarily utilizing pulmonary arterial endothelial cells as a representative hypoxic cell type, we identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210 (miR-210). ISCU1/2 facilitate the assembly of iron-sulfur clusters, prosthetic groups that are critical for electron transport and mitochondrial oxidation-reduction reactions. Under in vivo conditions of upregulating miR-210 and repressing ISCU1/2, the integrity of iron-sulfur clusters is disrupted. In turn, by repressing ISCU1/2 during hypoxia, miR-210 decreases the activity of prototypical iron-sulfur proteins controlling mitochondrial metabolism, including Complex I and aconitase. Consequently, miR-210 represses mitochondrial respiration and associated downstream functions. These results identify important mechanistic connections among microRNA, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to cellular stress.
Nucleic acids research, 2014
The DiseaseConnect (http://disease-connect.org) is a web server for analysis and visualization of... more The DiseaseConnect (http://disease-connect.org) is a web server for analysis and visualization of a comprehensive knowledge on mechanism-based disease connectivity. The traditional disease classification system groups diseases with similar clinical symptoms and phenotypic traits. Thus, diseases with entirely different pathologies could be grouped together, leading to a similar treatment design. Such problems could be avoided if diseases were classified based on their molecular mechanisms. Connecting diseases with similar pathological mechanisms could inspire novel strategies on the effective repositioning of existing drugs and therapies. Although there have been several studies attempting to generate disease connectivity networks, they have not yet utilized the enormous and rapidly growing public repositories of disease-related omics data and literature, two primary resources capable of providing insights into disease connections at an unprecedented level of detail. Our DiseaseConne...
Journal of Clinical Investigation, 1997
Vessel injury and thrombus formation are the cause of most ischemic coronary syndromes and, in th... more Vessel injury and thrombus formation are the cause of most ischemic coronary syndromes and, in this setting, activated platelets stimulate platelet recruitment to the growing thrombus. Recently, a constitutive nitric oxide synthase (NOS) has been identified in human platelets. To further define the capacity of platelets to produce nitric oxide (NO), as well as to study the role of this NO in platelet recruitment, we adapted a NO-selective microelectrode for use in a standard platelet aggregometer, thereby permitting simultaneous measurement of platelet aggregation and NO production. Treatment of platelets with the NO synthase inhibitor -NG-nitroarginine methyl ester (L-NAME), reduced NO production by 92+/-8% in response to 5 microM ADP compared to control but increased aggregation by only 15+/-2%. In contrast, L-NAME had a more pronounced effect on platelet recruitment as evidenced by a 35+/-5% increase in the extent of aggregation, a 33+/-3% decrease in cyclic GMP content, and a 31+/-5% increase in serotonin release from a second recruitable population of platelets added to stimulated platelets at the peak of NO production. To study platelet recruitment accurately, we developed an assay that monitors two platelet populations simultaneously. Nonbiotinylated platelets were incubated with L-NAME or vehicle and activated with ADP. At peak NO production, biotinylated platelets were added. As measured by three-color flow cytometry, there was a 56+/-11% increase in the number of P selectin- positive platelets in the nonbiotinylated population treated with L-NAME as compared to control. When biotinylated platelets were added to the L-NAME-treated nonbiotinylated population, the number of P selectin positive biotinylated plate-lets increased by 180+/-32% as compared to biotinylated platelets added to the control. In summary, stimulated platelets produce NO that modestly inhibits platelet activation but markedly inhibits additional platelet recruitment. These data suggest that platelet-derived NO may regulate platelet recruitment to a growing thrombus.
Circulation, Jan 8, 2014
The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldo... more The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension, suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in pulmonary arterial hypertension. Patients with pulmonary arterial hypertension, rats with Sugen/hypoxia-pulmonary arterial hypertension, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone lev...
Hemostasis is the result of interdependent and complex systemic and local endothelial pathways th... more Hemostasis is the result of interdependent and complex systemic and local endothelial pathways that govern vascular integrity and rheology. A striking feature of hypercoagulable conditions is the focal nature of the resultant thrombotic pathology. Such disorders in hemostasis may be associated with distinct vascular beds, thus implying that the relative combined contribution of individual regulatory pathways may be specific and/or
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Papers by Joseph Loscalzo