Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome

Nicholls, Stephen J.; Kastelein, John J.P.; Schwartz, Gregory G.; Bash, Dianna; Rosenson, Robert S.; Cavender, Matthew A.; Brennan, Danielle M.; Köenig, Wolfgang; Jukema, J. Wouter; Nambi, Vijay; Wright, R. Scott; Menon, Venu; Lincoff, A. Michael; Nissen, Steven E.

doi:10.1001/jama.2013.282836

Cited by 297 publications

(189 citation statements)

References 21 publications

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“…Thus, inhibition of the enzyme is contemplated as a possibly valid therapeutic approach to treating cardiovascular disease. Although recent trials testing the effect of varespladib, an inhibitor of the closely related enzyme sPLA 2 -IIA that also can block, at least in part, sPLA 2 -V, provided discouraging results (85,86), our results implicating sPLA 2 -V in regulating phagocytosis in human macrophages suggest that possible cardiovascular benefits of inhibiting sPLA 2 -V could compromise innate immune responses to microorganism infection and, hence, delay resolution of inflammation.…”

Section: Discussionmentioning

confidence: 66%

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Rubio

Rodríguez

Gil-de-Gómez

et al. 2015

The Journal of Immunology

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Studies on the heterogeneity and plasticity of macrophage populations led to the identification of two major polarization states: classically activated macrophages or M1, induced by IFN-γ plus LPS, and alternatively activated macrophages, induced by IL-4. We studied the expression of multiple phospholipase A2 enzymes in human macrophages and the effect that polarization of the cells has on their levels. At least 11 phospholipase A2 genes were found at significant levels in human macrophages, as detected by quantitative PCR. None of these exhibited marked changes after treating the cells with IFN-γ plus LPS. However, macrophage treatment with IL-4 led to strong upregulation of the secreted group V phospholipase A2 (sPLA2-V), both at the mRNA and protein levels. In parallel with increasing sPLA2-V expression levels, IL-4–treated macrophages exhibited increased phagocytosis of yeast-derived zymosan and bacteria, and we show that both events are causally related, because cells deficient in sPLA2-V exhibited decreased phagocytosis, and cells overexpressing the enzyme manifested higher rates of phagocytosis. Mass spectrometry analyses of lipid changes in the IL-4–treated macrophages suggest that ethanolamine lysophospholipid (LPE) is an sPLA2-V–derived product that may be involved in regulating phagocytosis. Cellular levels of LPE are selectively maintained by sPLA2-V. By supplementing sPLA2-V–deficient cells with LPE, phagocytosis of zymosan or bacteria was fully restored in IL-4–treated cells. Collectively, our results show that sPLA2-V is required for efficient phagocytosis by IL-4–treated human macrophages and provide evidence that sPLA2-V–derived LPE is involved in the process.

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Section: Discussionmentioning

confidence: 66%

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Rubio

Rodríguez

Gil-de-Gómez

et al. 2015

The Journal of Immunology

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“…Initial studies demonstrated that varespladib, a nonspecific pan-sPLA 2 inhibitor, reduced activity of sPLA 2 -IIA by more than 90%, in addition to lowering low-density-lipoprotein cholesterol and C-reactive protein in patients with stable coronary disease and acute coronary syndrome. Surprisingly, varespladibinduced sPLA 2 inhibition did not reduce cardiovascular ischemic complications and resulted in an excess rate of myocardial infarction and stroke in patients with acute coronary syndromes [8]. Moreover, inhibition of sPLA 2 showed no overall survival benefit in septic patients [9].…”

Section: Europe Pmc Funders Author Manuscripts Europe Pmc Funders Autmentioning

confidence: 98%

“…Pathologic studies demonstrated the presence of sPLA 2 isoforms in atherosclerotic lesions and myocardial regions that have sustained ischemic injury [7]. Unexpectedly, inhibition of sPLA 2 in patients with acute coronary syndromes resulted in an excess rate of myocardial infarction and stroke [8] and showed no overall survival benefit in patients with severe sepsis [9]. These studies clearly suggest that the pathophysiologic roles of sPLA 2 are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil effector responses are suppressed by secretory phospholipase A2 modified HDL

2015

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“…However, recent clinical trials using darapladib, an Lp-PLA2 inhibitor, failed to exhibit any beneficial effects on clinical outcome in patients with stable coronary heart disease (STABILITY) or acute coronary syndromes (SOLID-TIMI 52) (40,41). Another phospholipase inhibitor, varespladib, also failed to produce beneficial effects and even caused an increase in cardiovascular events (42).…”

Section: Presentmentioning

confidence: 99%

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

et al. 2017

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SummaryEven two centuries after they were first described, atherosclerosis and atherothrombosis remain among the leading causes of death worldwide. Over the last decades it has become clear that atherosclerosis is not only a lipid-driven disease but also a multifactorial process largely driven by inflammatory mediators, an insight that has instigated additional research and drug development focussing on anti-inflammatory therapies. In this review, we will provide a brief historical overview, followed by a more general synopsis of the range of currently available state-of-the-art therapies for atherosclerosis and atherothrombosis. Finally, we will highlight some of the promising therapeutic strategies that are currently under intense investigation. We believe that the next years will witness highly interesting developments and clinical trials investigating yet more novel therapies, and at the same time looking into potential combinations of all available therapies. This prospect closes in on the ultimate goal, which is to reduce the residual risk that still persists despite present therapeutic options.

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Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome

Cited by 297 publications

References 21 publications

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Neutrophil effector responses are suppressed by secretory phospholipase A2 modified HDL

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

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