scholarly journals COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification

2020 ◽  
Vol 21 (23) ◽  
pp. 8917
Author(s):  
Francesco Vieceli Dalla Sega ◽  
Francesca Fortini ◽  
Paolo Cimaglia ◽  
Luisa Marracino ◽  
Elisabetta Tonet ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Clinical Analysis ◽  
Dystrophic Calcification ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Induced Apoptosis ◽  
Human Aortic Valve

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; p < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-β-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression.

scholarly journals Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

2020 ◽  
Author(s):  
Michael A. Raddatz ◽  
Tessa M. Huffstater ◽  
Matthew R. Bersi ◽  
Bradley I. Reinfeld ◽  
Matthew Z. Madden ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Macrophage Polarization ◽  
Valve Disease ◽  
Dystrophic Calcification ◽  
Cell Secretion ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Macrophage Recruitment

AbstractObjectiveMacrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the Notch1+/- model of calcific aortic valve disease.Approach and ResultsMacrophages in wild-type and Notch1+/- murine aortic valves were characterized by flow cytometry. Macrophages in Notch1+/- aortic valves had increased expression of MHCII. We then used bone marrow transplants to test if differences in Notch1+/- macrophages drive disease. Notch1+/- mice had increased valve thickness, macrophage infiltration, and M1-like macrophage polarization regardless of transplanted bone marrow genotype. In vitro approaches confirm that Notch1+/- aortic valve cells promote macrophage invasion as quantified by migration index and M1-like polarization quantified by Ly6C and CCR2 positivity regardless of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification by decreasing abundance of the STAT3β isoform.ConclusionsThis study reveals that Notch1+/- aortic valve disease involves increased macrophage recruitment and polarization driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification through STAT3 splicing changes. Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.Graphical Abstract

scholarly journals Evaluation of Anticonvulsant Activity of Dual COX-2/5-LOX Inhibitor Darbufelon and Its Novel Analogues

2021 ◽  
Vol 89 (2) ◽  
pp. 22
Author(s):  
Mariia Mishchenko ◽  
Sergiy Shtrygol’ ◽  
Andrii Lozynskyi ◽  
Semen Khomyak ◽  
Volodymyr Novikov ◽  
...  
Keyword(s):  
Drug Design ◽  
Anticonvulsant Activity ◽  
Inflammatory Activity ◽  
Significant Protection ◽  
Protection Level ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Target Agent

Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.

scholarly journals Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

2017 ◽  
Vol 114 (7) ◽  
pp. 1631-1636 ◽  
Author(s):  
Qingchun Zeng ◽  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Yufeng Zhai ◽  
...  
Keyword(s):  
Aortic Valve ◽  
High Fat Diet ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
High Fat ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Valve Lesions ◽  
Osteogenic Factors

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

The role of celecoxib as a potential inhibitor in the treatment of inflammatory diseases - a review

2021 ◽  
Vol 28 ◽  
Author(s):  
Josiane Viana Cruz ◽  
Joaquín María Campos Rosa ◽  
Njogu Mark Kimani ◽  
Silvana Giuliatti ◽  
Cleydson Breno Rodrigues dos Santos
Keyword(s):  
Side Effects ◽  
Inflammatory Diseases ◽  
Structural Basis ◽  
Potential Inhibitor ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

: This article presents a simplified view of celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) has, predominantly, two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role that is related to homeostatic effects in renal and platelets, while the latter is mainly responsible for induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and without side effects. To this end, of the generation of non-steroidal anti-inflammatory drugs from “coxibs”, celecoxib is the only potent selective COX-2 inhibitor that is still commercially available. Thus, the compound celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for COX-2 enzyme. In this review, we provide highlights where such inhibition should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs) which act as COX-2 inhibitors with lesser side effects on the human body.

scholarly journals Peran Kurkumin Sebagai Terapi Pada Osteoartritis

2020 ◽  
Vol 2 (1) ◽  
pp. 106-110
Author(s):  
Rilianda Abelira
Keyword(s):  
Peptic Ulcer ◽  
Side Effects ◽  
Old Age ◽  
Cyclooxygenase 2 ◽  
Tnf Α ◽  
The World ◽  
Inflammatory Drugs ◽  
Digestive Disorders ◽  
Cox 2 ◽  
Anti Inflammatory

Osteoartritis (OA) merupakan salah satu penyakit penyakit degeneratif atau geriatri yang disebabkan adanya inflamasi yang melibatkan kartilago, lapisan sendi, ligamen, dan tulang yang akibatnya dapat menyebabkan nyeri dan kekakuan pada sendi. Epidemiologi OA di didunia sekitar 15% dengan usia diatas 65-75 dan diperkirakan pada tahun 2020 penderita osteoarthritis akan meningkat 11,6 juta penderita. Kejadian OA di Indonesia dari tahun 1990 hingga 2010 telah mengalami peningkatan sebanyak 44,2% dan berdasarkan usia di Indonesia cukup tinggi dengan 65% pada usia tua (lansia) atau lebih dari 61 tahun. Pengobatan secara farmakologis untuk OA dengan menggunakan Obat Anti Inflamasi Non-Steroid (OAINS) salah satu contohnya adalah meloksikam. Namun, efek samping penggunaan OAINS dapat menimbulkan beberapa masalah seperti timbulnya ulkus peptikum dan gangguan pencernaan. Hal ini menyebabkan sedang dikembangkannya pengobatan herbal untuk OA yang harapannya dapat menjadi pengobatan utama dalam mengatasi OA dengan menggunakan kurkumin. Kurkumin berperan sebagai antiinflamasi dalam kunyit putih dengan menurunkan aktivitas cyclooxygenase 2(COX-2), lipoxygenase dan menghambat produksi sitokin seperti TNF-α, interleukin (IL). Osteoarthritis (OA) is a degenerative or geriatric disease that is caused by inflammation involving cartilages, joint lining, ligaments, and bones which can cause pain and stiffness in the joints. Epidemiology of OA in the world around 15% with ages above 65-75 and it is estimated in 2020, osteoarthritis will increase by 11.6 million. The incidence of OA in Indonesia from 1990 to 2010 has increased by 44.2% and by age in Indonesia is quite high with 65% in old age (elderly) or more than 61 years. Treatment for OA is using non-steroidal anti-inflammatory drugs (NSAIDs), such as meloxicam. However, side effects of NSAID use can cause several problems such as the emergence of peptic ulcer and digestive disorders. This has led to the development of herbal treatments for OA which hopes to become the main treatment in overcoming OA by using curcumin. Curcumin acts as an anti-inflammatory in white turmeric by reducing the activity of cyclooxygenase 2 (COX-2), lipoxygenase and inhibiting the production of cytokines such as TNF-α, interleukin (IL).

COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease

2003 ◽  
Vol 12 (1) ◽  
pp. 12
Author(s):  
W.A. Ray ◽  
C.M. Stein ◽  
J.R. Daugherty ◽  
K. Hall ◽  
P.G. Arbogast ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory

scholarly journals Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves

2018 ◽  
Vol 96 (2) ◽  
pp. 208-214 ◽  
Author(s):  
Ateeque Siddique ◽  
Bin Yu ◽  
Kashif Khan ◽  
Ryan Buyting ◽  
Hamood Al-Kindi ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Wnt Signaling ◽  
Quantitative Polymerase Chain Reaction ◽  
Disease Process ◽  
Receptor Expression ◽  
Cellular Mechanisms ◽  
Aortic Valves ◽  
Major Player ◽  
Frizzled Receptors ◽  
Human Aortic Valve

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.

Abstract P372: U.S. National Estimates of Prescription Nonsteroidal Anti-inflammatory Drugs Among Patients With Cardiovascular Disease

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Andrew Y Hwang ◽  
Steven M Smith
Keyword(s):  
Heart Disease ◽  
Boxed Warning ◽  
Self Report ◽  
Cross Sectional ◽  
Increased Risk ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cv Disease ◽  
Prescription Nsaid

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, fever, and inflammation, but their ubiquitous use has led to concerns over increased risk of adverse cardiovascular (CV) events, particularly in patients with established CV disease (CVD). In 2005, the FDA revised labels for all NSAIDs to include a boxed warning highlighting the potential for increased CV risk. However, little is known regarding real-world prescribing of NSAIDs among patients with CVD. Our objective was to characterize the use of prescription NSAIDs among patients with CVD from 1988-2016 in the U.S. Methods: Using cross-sectional National Health and Nutrition Examination Survey (NHANES) data from 1988-1994 and 1999-2016, we included participants aged ≥18 years with hypertension (defined by self-report, mean blood pressure ≥140/90, or use of an antihypertensive medication), or aged ≥20 years with ≥1 of the following self-reported heart disease conditions: congestive heart failure (CHF), coronary heart disease (CHD), angina, myocardial infarction (MI), or stroke. Survey-weighted data were analyzed to assess prevalence and trends of prescription NSAID use within each CVD population in 6-year examination periods. Results: Overall, prescription NSAID use declined among all U.S. CVD populations over the study period. Prevalence of prescription NSAID use was highest during the 1999-2004 examination years, but thereafter, declined during the 2005-2010 examination years for those with hypertension (13.9% to 8.8%), CHF (14.6% to 8.5%), CHD (16.3% to 7.0%), angina (17.6% to 9.73%), MI (16.1% to 8.2%), and stroke (15.7% to 8.8%). Use of prescription NSAIDs since the 2005-2010 examination years has remained consistent in all CVD populations. These decreases were driven in part by reduced use of COX-2-selective NSAIDs, whereas non-selective NSAID use among all CVD populations was relatively steady from 1999 to 2016. Conclusions: Prescription NSAID use among patients with CVD appears to have declined from 1988 to 2016, primarily because of less COX-2 NSAID use following removal of 2 approved agents. Otherwise, the prevalence of prescription NSAIDs has remained somewhat stable and relatively high among these high-risk CV populations. Our results suggest additional efforts may be needed to limit the use of NSAIDs among patients with CVD, given that these agents are known to be associated with adverse CVD outcomes.

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