Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation.
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ABSTRACT:
SUBMITTER: Mitchell JA
PROVIDER: S-EPMC7978428 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages.In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I2 and prostaglandin E2, elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, ?-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants.Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.
| S-EPMC4006304 | biostudies-literature
Project description:BackgroundAlthough the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to atherogenesis.Methods and resultsDeletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by approximately 30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low-density lipoprotein receptor knockouts were unaltered in TC knockouts.ConclusionsMacrophage-COX-2, primarily a source of thromboxane A(2) and prostaglandin (PG)E(2), promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective prostacyclin. TC COX-2 does not detectably influence TC development or function or atherogenesis in mice.
| S-EPMC2909762 | biostudies-literature
Project description:Prostaglandin (PG) E(2) is formed from PGH(2) 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 11alpha-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 (PGI(2)) 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 PGI(2) and thromboxane A(2) to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF(1alpha), but not 2,3-dinor-TxB(2), was increased in mPGES-1(-/-) LDLR(-/-)s. mPGES-1-derived PGE(2) 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 PGH(2) to augment formation of PGI(2). 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 PGI(2).
| S-EPMC1566188 | biostudies-literature
Project description:Cyclooxygenase (COX)-derived prostanoids (PGs) are involved in blood pressure homeostasis. Both traditional nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit COX-1 and COX-2 and NSAIDs designed to be selective for inhibition of COX-2 cause sodium retention and elevate blood pressure.To elucidate the role of COX-2 in blood pressure homeostasis using COX-1>COX-2 mice, in which the COX-1 expression is controlled by COX-2 regulatory elements.COX-1>COX-2 mice developed systolic hypertension relative to wild types (WTs) on a high-salt diet (HSD); this was attenuated by a PGI(2) receptor agonist. HSD increased expression of COX-2 in WT mice and of COX-1 in COX-1>COX-2 mice in the inner renal medulla. The HSD augmented in all strains urinary prostanoid metabolite excretion, with the exception of the major PGI(2) metabolite that was suppressed on regular chow and unaltered by the HSD in both mutants. Furthermore, inner renal medullary expression of the receptor for PGI(2), but not for other prostanoids, was depressed by HSD in WT and even more so in both mutant strains. Increasing osmolarity augmented expression of COX-2 in WT renal medullary interstitial cells and again the increase in formation of PGI(2) observed in WTs was suppressed in cells derived from both mutants. Intramedullary infusion of the PGI(2) receptor agonist increased urine volume and sodium excretion in mice.These studies suggest that dysregulated expression of the COX-2 dependent, PGI(2) biosynthesis/response pathway in the renal inner renal medulla undermines the homeostatic response to a HSD. Inhibition of this pathway may contribute directly to the hypertensive response to NSAIDs.
| S-EPMC2818801 | biostudies-literature
Project description:ObjectiveThe purpose of this study was to determine the role of the endothelial glucocorticoid receptor in the pathogenesis of atherosclerosis.Approach and resultsControl mice and mice lacking the endothelial glucocorticoid receptor were bred onto an Apoe knockout background and subjected to high-fat diet feeding for 12 weeks. Assessment of body weight and total cholesterol and triglycerides before and after the diet revealed no differences between the 2 groups of mice. However, mice lacking the endothelial glucocorticoid receptor developed more severe atherosclerotic lesions in the aorta, brachiocephalic artery, and aortic sinus, as well as a heightened inflammatory milieu as evidenced by increased macrophage recruitment in the lesions.ConclusionsThese data suggest that the endothelial glucocorticoid receptor is important for tonic inhibition of inflammation and limitation of atherosclerosis progression in this model.
| S-EPMC4375730 | biostudies-literature
Project description:Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
| S-EPMC3491520 | biostudies-other
Project description:AimsContinuous infusion of prostacyclin analogues improves survival in advanced pulmonary arterial hypertension. In addition to its vasodilatory effects, prostacyclin has the potential to decrease inflammation, thrombosis, and smooth muscle proliferation. The aim of this retrospective study was to determine whether pathological data support the ability of prostanoids to prevent progression of vascular disease.Methods and resultsTwenty-two autopsied patients with World Health Organization category 1 pulmonary arterial hypertension (primarily idiopathic and connective tissue disease-associated) were divided into those who received long-term prostacyclin (n = 12, PG-long, mean treatment 3.9 years) and those who received 0-1 month of prostacyclin (n = 10, PG-short). Surprisingly, PG-long patients had larger plexiform lesions (P < 0.05), with no decrease in medial and intimal thicknesses as compared with PG-short patients. Plexiform lesion size and density increased with increasing treatment time. Also, PG-long patients had fewer platelet thrombi and more frequent acute diffuse alveolar haemorrhage. Quantification of macrophages and T cells revealed no differences in inflammatory infiltrates.ConclusionAlthough long-term prostacyclin therapy may have an antithrombotic effect in addition to its vasodilatory actions, it was not associated with the prevention of advanced vascular lesions. The mechanism by which prostacyclin analogues improve survival in pulmonary arterial hypertension remains uncertain.
| S-EPMC4143476 | biostudies-literature
Project description:ObjectiveThe c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLR(-/-) mice.Methods and resultsTo assess the function of JNK1 in early atherogenesis, we measured EC apoptosis and lesion formation in LDLR(-/-) or LDLR(-/-)/JNK1(-/-) mice exposed to a high fat diet for 6 weeks. En face staining using antibodies that recognise active, cleaved caspase-3 (apoptosis) or using Sudan IV (lipid deposition) revealed that genetic deletion of JNK1 reduced EC apoptosis and lesion formation in hypercholesterolemic mice. By contrast, although EC apoptosis was enhanced in LDLR(-/-)/MKP-1(-/-) mice compared to LDLR(-/-) mice, lesion formation was unaltered.ConclusionWe conclude that JNK1 is required for EC apoptosis and lipid deposition during early atherogenesis. Thus pharmacological inhibitors of JNK may reduce atherosclerosis by preventing EC injury as well as by influencing foam cell formation.
| S-EPMC4104040 | biostudies-literature
Project description:Atherosclerosis is the leading cause of cardiovascular diseases, which is also the primary cause of mortality among diabetic patients. Endothelial cell (EC) dysfunction is a critical early step in the development of atherosclerosis and aggravated in the presence of concurrent diabetes. Although the heterogeneity of the organ-specific ECs has been systematically analyzed at the single-cell level in healthy conditions, their transcriptomic changes in diabetic atherosclerosis remain largely unexplored. Here, we carried out a single-cell RNA sequencing (scRNA-seq) study using EC-enriched single cells from mouse heart and aorta after 12 weeks feeding of a standard chow or a diabetogenic high-fat diet with cholesterol. We identified eight EC clusters, three of which expressed mesenchymal markers, indicative of an endothelial-to-mesenchymal transition (EndMT). Analyses of the marker genes, pathways, and biological functions revealed that ECs are highly heterogeneous and plastic both in normal and atherosclerotic conditions. The metabolic transcriptomic analysis further confirmed that EndMT-derived fibroblast-like cells are prominent in atherosclerosis, with diminished fatty acid oxidation and enhanced biological functions, including regulation of extracellular-matrix organization and apoptosis. In summary, our data characterized the phenotypic and metabolic heterogeneity of ECs in diabetes-associated atherogenesis at the single-cell level and paves the way for a deeper understanding of endothelial cell biology and EC-related cardiovascular diseases.
| S-EPMC8170046 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is characterized by low HDL cholesterol, but the activity of the HDL-associated antioxidative enzyme paraoxonase-1 (PON-1) remains unclear. To determine the association of PON-1 with suspected NAFLD, we measured serum enzyme activity in 7,622 participants of the Prevention of Renal and Vascular End-Stage Disease cohort. A fatty liver index (FLI) ≥60, a proxy of NAFLD, was present in 2,083 participants (27.3%) and coincided with increased prevalence of T2D, metabolic syndrome (MetS), (central) obesity, elevated triglycerides, and low HDL cholesterol (all P < 0.001). In men and women combined, serum PON-1 activity did not vary according to elevated FLI (P = 0.98), whereas in men with elevated FLI PON-1 activity was increased (P = 0.016). In multivariable linear regression analyses (adjusted for age, sex, T2D, MetS, alcohol use, and smoking), PON-1 activity was unexpectedly associated with elevated FLI (β = 0.083; P < 0.001). In a sensitivity analysis (n = 5,126) that excluded subjects with positive cardiovascular history, impaired estimated glomerular filtration rate, elevated urinary albumin excretion, and drug use, PON-1 activity was also independently associated with elevated FLI (β = 0.045; P = 0.017). These results indicate that PON-1 is paradoxically maintained and may even be increased in NAFLD despite inverse associations with metabolic disorders and low HDL cholesterol.
| S-EPMC6314263 | biostudies-literature