COX-2 Inhibitors And Cardiovascular Risk

Salzberg, Daniel J.; Weir, Matthew R.

doi:10.1007/1-4020-5688-5_7

Cited by 13 publications

(12 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Under this scenario, the elevation of NFAT activity and increased downstream gene expression such as COX-2 may actually help to prevent lipid deposition and thrombosis, therefore exerting a beneficial effect. This reminds of major cardiovascular complications people encountered when the COX2 inhibitor was initially developed and administered (Salzberg and Weir, 2007). Clearly, further detailed analyses regarding the relevance of IRAK-1 mediated NFATc4 regulation in various cells such as endothelial cells, smooth muscle cells, mononuclear cells, and T cells are warranted.…”

Section: Discussionmentioning

confidence: 99%

The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT

Wang¹,

Fasciano²,

Li³

2008

Molecular Immunology

View full text Add to dashboard Cite

IRAK-1 is a critical modulator regulating innate immunity signaling processes. However, the physiological substrates for IRAK-1 remain poorly defined. In this report, we have demonstrated that IRAK-1 is a kinase responsible for the constitutive phosphorylation and inactivation of the Nuclear Factor of Activated T-cell (NFAT). Expression of IRAK-1 suppressed NFAT reporter activity. Correspondingly, the levels of both nuclear NFATc1 and NFATc4 were constitutively elevated in IRAK-1 -/-cells. Furthermore, the phosphorylation of NFATc4 at the S 168 PS 170 P site was significantly diminished in IRAK-1 -/-cells. Mechanistically, we observed that IRAK-1 interacted with NFATc4 via the C-terminus of IRAK-1 and the N-terminal NHR region of NFATc4. IRAK-1 mutants that ablated either its kinase activity or its interaction with NFATc4 failed to suppress NFAT reporter activity. The expression level of COX-2, which is under the control of NFAT, was elevated in IRAK-1 -/-cells. Functionally, ApoE -/-/IRAK-1 -/-mice were protected from high-fat-diet induced hypertension and atherosclerosis. Taken together, our findings reveal NFAT molecules as novel physiological targets for IRAK-1.

show abstract

Section: Discussionmentioning

confidence: 99%

The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT

Wang¹,

Fasciano²,

Li³

2008

Molecular Immunology

View full text Add to dashboard Cite

show abstract

“…Nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) and cyclo-oxygenase-2 (COX-2) selective inhibitors have been demonstrated to increase systemic blood pressure (BP) levels, predominantly systolic BP (SBP) [1][2][3] COX-2 inhibitors have also been associated with increases in cardiovascular (CV) events in some patients in comparison with patients receiving placebo and the nsNSAID naproxen in some clinical trials [4][5][6][7][8][9] and to matched subjects not receiving these agents in observational cohorts [10][11][12]. A number of hypotheses have been proposed to explain mechanisms underlying this increase in CV risk, including enhancement of thrombosis and development of hypertension [13][14][15].…”

mentioning

confidence: 99%

Blood Pressure and Cardiovascular Outcomes in Patients Taking Nonsteroidal Antiinflammatory Drugs

Krum

Swergold

Gammaitoni

et al. 2011

Cardiovascular Therapeutics

Self Cite

View full text Add to dashboard Cite

SUMMARY Introduction:The increased thrombotic cardiovascular (CV) risk in trials of cyclooxygenase-2 (COX-2) inhibitors versus placebo, and the apparent similar risk with nonsteroidal antiinflammatory drugs (NSAIDs), may be related to their potential to elevate blood pressure (BP). Aims: We evaluated the relationship between baseline BP and change in BP on CV events (CVEs) in patients receiving NSAIDs or COX-2 inhibitors in the prospective randomized, double-blind, Multinational Etoricoxib and Diclofenac Arthritis Long-term Program (N = 34,701) comparing etoricoxib 60 or 90 mg or diclofenac 150 mg daily for a mean duration of 18 months. The main outcome measure was confirmed thrombotic CVEs. The Antiplatelet Trialists' Collaboration endpoint, all-cause mortality, CV/congestive heart failure (CHF) mortality, and CHF incidence were similarly evaluated. Results: We found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001). Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P = 0.016) except CV/CHF mortality (P = 0.054). There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P = 0.019). Only CHF risk (P = 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4. These findings were not meaningfully altered after covariate adjustment for baseline CV risk. Conclusions: Baseline BP, but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The CV risk of COX-2s and NSAIDs did not appear to be related to the BPelevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship.

show abstract

“…In either case, it seems prudent to recommend that subjects who are at higher risk for a cardiovascular event and receiving a COXinhibitor should also be treated with low dose ASA with close follow up of blood pressure and efficacious use of antihypertensive medications. Finally, modest dietary salt restriction may help lessen the effects of COX-inhibitors on blood pressure [61].…”

Section: Cox-inhibitorsmentioning

confidence: 99%

Clinical Pharmacology and Vascular Risk

Silvestrelli

Corea²,

Micheli³

et al. 2010

TONEUJ

View full text Add to dashboard Cite

Pharmacological treatment and several drugs of abuse have been associated with ischemic heart disease (IHD) and cerebrovascular diseases (CVD). However, there is a paucity of data on the independent risk of vascular disease (VD) associated with pharmacological treatment and no controlled trials demonstrating a reduction in risk with abstinence.Information about IHD and CVD-related drug abuse is mainly limited to epidemiological studies focused on urban populations. The potential link between some pharmacological treatments (estrogen, some oncologic drugs and some atypical antipsychotics) and cerebrovascular adverse events was analyzed, but disagreement about an association persists. Drugs of abuse, including cocaine, amphetamines and heroin, have been associated with an increased vascular risk.These drugs can cause abrupt changes in blood pressure, vasculitic-type changes, lead to embolization caused by infective endocarditis, and hemostatic and hematologic abnormalities that can result in increased blood viscosity and platelet aggregation. Long-term treatment strategies based on medication, psychological support, and outreach programs play an important role in treatment of drug dependency.In these last years public interest in risk factors for VD has been constantly increasing and the successful identification and management of pharmacological treatment and drug abuse can be challenging. One of the major public health issues for the future will be to focus more on new vascular risk factor recognition and management.The objective of this chapter is to review the relevance of IHD and CVD associated with various pharmacological treatments and drug abuse with focusing on ischemic disease. This chapter reports the clinical evidence of this association and analyzes the experimental role of new drugs as a growing risk factor of VD with the hypothetical new association. In conclusion, in this chapter great attention is paid to evaluating the scientific and real evidence of cerebrovascular effect and drug use and abuse so as to identify a new groups of "modifiable" risk factors.

show abstract

COX-2 Inhibitors And Cardiovascular Risk

Cited by 13 publications

References 45 publications

The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT

The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT

Blood Pressure and Cardiovascular Outcomes in Patients Taking Nonsteroidal Antiinflammatory Drugs

Clinical Pharmacology and Vascular Risk

Contact Info

Product

Resources

About