Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice

Zhang, Yu; Crichton, Irene; Tang, Soon Yew; Hui, Yiqun; Ricciotti, Emanuela; Levin, Mark; Lawson, John A.; Puré, Ellen; FitzGerald, Garret A.

doi:10.1073/pnas.1115313109

Cited by 46 publications

(49 citation statements)

References 51 publications

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“…145% Inducible whole body COX-2 KO did not result in blood pressure or lipid changes. There was no excess atherosclerosis in mice with combined COX-2 and FLAP KO (2050). Macrophage-only KO by Cre-Lox in LDLR-null mice decreased atherosclerosis 25% at 6 mo but BMT of COX-2 KO marrow showed no effect in apoE KO mice (1284).…”

Section: Calcium Signaling Ion Channels and Weibel-palade Body Exocmentioning

confidence: 93%

“…COX-2 and 5-LO apparently compete for free AA. Presumably, loss of COX-2 competition in COX-2 KO animals increased AA supply to the leukotriene pathway and then allowed KO of FLAP to decrease atherosclerosis (2050). Alternatively, lack of COX-2 could also result in decreased PGE 2 production in leukocytes during later stages of inflammation.…”

Section: -Lo and The Leukotrienesmentioning

confidence: 99%

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Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

379

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Calcium Signaling Ion Channels and Weibel-palade Body Exocmentioning

confidence: 93%

Section: -Lo and The Leukotrienesmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

379

344

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“…112 COX-2 null mice actually had the same phenotypic consequence as deletion of the prostacyclin IP receptor, with accelerated atherogenesis. 113,114 Instead, deletion of vascular mPGES1 limits the atherogenic response and prevents the thrombotic consequences associated with COX-2 selective antagonism. 115 A central role was revealed for mPGES1 from myeloid cells to the atherogenic response in inflammatory states, suggesting that it can be targeted to protect against cardiovascular consequences.…”

Section: Pge 2 In Other Aspects Of the Metabolic Syndromementioning

confidence: 99%

PGE2, Kidney Disease, and Cardiovascular Risk

Nasrallah

Hassouneh

Hébert

2016

Journal of the American Society of Nephrology

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An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE 2 in these events. This review summarizes the role of PGE 2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE 2 signaling in hypertension and diabetes, and outlines the contribution of PGE 2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE 2 could lead to new avenues to improve therapeutic options and disease management strategies. 27: 666-676, 201627: 666-676, . doi: 10.1681 Accelerated cardiovascular disease is the leading cause of mortality in patients with kidney disease. 1,2 This implies that kidney disease has a major effect on global cardiovascular risk, affecting fluid (volume, BP), electrolyte, and acid base balance, among many other cardiovascular risk factors. In fact, renal transplantation ameliorates cardiovascular risk, improves quality of life, and reduces mortality. 2 PGs are important homeostatic regulators of kidney function. PGE 2 is the major product of cyclooxygenase (COX)-2 and microsomal PGE synthase 1 (mPGES1), and both of these enzymes are elevated in renal diseases. [3][4][5][6][7][8][9][10] PGE 2 binds four EP receptors (EP 1-4 ) to activate G protein signaling responses. Figure 1 illustrates the COX pathway leading to PGE 2 , as well as its target receptors. These receptors are often coexpressed in cells and usually have opposing effects (protective and harmful). PGE 2 acting on EP can alter vascular tone and influence renal blood flow and hemodynamics. 11-15 PGE 2 also stimulates the macula densa to activate the renin-angiotensin-aldosterone system, a key mediator of kidney injury. [16][17][18][19] Inflammatory, immune, and oxidative stress responses are influenced by PGE 2 , which are reported to alter growth, fibrosis, and apoptosis in renal cells. 20-26 PGE 2 also contributes to disturbances in collecting duct salt and water transport in polyuric diseases, 19,[27][28][29] and b cell defects in sodium and potassium handling associated with type I distal renal tubule acidosis. 30 PGE 2 /EP 4 also compensates for the loss of vasopressin V2 receptors in mouse diabetes insipidus. 28 Although attempts to block PGE 2 using COX-2 or mPGES1 inhibitors have failed, selective inhibition of EP receptors may prove to be quite useful in controlling the deleterious effects of COX-2/mPGES1/PGE 2 , while leaving the protective responses intact. EP 1 mediates many of the pathologic effects of PGE 2 in kidne...

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“…On the same trend, in high fat-fed LDLR deficient mice, pharmacological inhibition of COX-2 with either selective (rofecoxib) or nonselective (indomethacin) or genetic macrophage-specific COX-2 ablation reduced atherosclerosis [206]. In contrast, COX-2 postnatal deletion on an apoE-deficient background accelerated atherosclerosis in a gender-independent manner [207]. COX-2 specific deletion in macrophages attenuated inflammation, but not atherosclerosis in apoE-deficient mice [208].…”

Section: Cyclooxygenasementioning

confidence: 91%

Enzymatic Targets in Atherosclerosis

Fuior¹,

Trusca²,

Roman³

et al. 2015

J Mol Genet Med

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Atherosclerosis, a prime cause of mortality across the developed societies, was targeted by diverse therapeutic strategies. These evolved in response to the complex etiology and evolution of the disease. Many enzymes are associated with atherosclerosis, either in the main stream of lipid biosynthesis and transport or in the collateral and intertwined pathways of oxidative stress, inflammation, vascular remodeling or chromatin stability and are therefore revised herein. Enzyme exploration led to important developments. At the beginning, there were the statins, derived as inhibitors of hydroxy-methyl-glutaryl CoA (HMG-CoA) reductase, currently used widely to decrease lipid levels. At the other end, the inhibitors of the recently discovered proprotein convertase subtilisin/kexin type 9 (PCSK9) are awaiting the validation in clinical trials with great hopes for the future. In between, one can find some palliatives, as aspirin, an inhibitor of cyclooxygenase (COX), but also many invalidated candidates. Classical pharmacological data and newer approaches, like genetic knockouts in murine atherosclerosis models, are reviewed in order to appreciate the involvement of a particular enzyme in atherogenesis. However, the pursuit of an efficacious drug has been long and, in many cases, disappointing. Conclusions can be drawn from the overview of both successes and failures, in a quest for the best.

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Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice

Cited by 46 publications

References 51 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

PGE2, Kidney Disease, and Cardiovascular Risk

Enzymatic Targets in Atherosclerosis

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