RESUMEN
Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/Drm is crucial in embryo-/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin-1 in atherosclerosis. Here we report that Gremlin-1 is highly expressed primarily by monocytes/macrophages in aortic atherosclerotic lesions of ApoE(-/-) mice and is secreted from activated monocytes and during macrophage development in vitro. Gremlin-1 reduces macrophage formation by inhibiting macrophage migration inhibitory factor (MIF), a cytokine critically involved in atherosclerotic plaque progression and vulnerability. Gremlin-1 binds with high affinity to MIF (KD = 54 nm), as evidenced by surface plasmon resonance analysis and co-immunoprecipitation, and reduces MIF-induced release of TNF-α from macrophages. Treatment of ApoE(-/-) mice with a dimeric recombinant fusion protein, mGremlin1-Fc, but not with equimolar control Fc or inactivated mGremlin1-Fc, reduced TNF-α expression, the content of monocytes/macrophages of atherosclerotic lesions, and attenuated atheroprogression. The present data disclose that Gremlin-1 is an endogenous antagonist of MIF and define a role for Gremlin-1/MIF interaction in atherosclerosis.
Asunto(s)
Apolipoproteínas E , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Oxidorreductasas Intramoleculares/biosíntesis , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/biosíntesis , Factores Inhibidores de la Migración de Macrófagos/genética , Macrófagos/patología , Ratones , Ratones Noqueados , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Both COVID-19 disease and cocaine consumption have prothrombotic and hypercoagulable effects and are associated with increased risk of cardiovascular events. We report the case of a patient with acute myocardial infarction in the setting of active COVID-19 disease and recent cocaine consumption. We hypothesize that COVID-19 and cocaine synergistically provoke cardiovascular events. Identifying COVID-19 disease and/or cocaine abuse as potential triggers of acute myocardial infarction can be crucial due to distinctive therapeutic consequences.
RESUMEN
In this case report we present a previously healthy 21-year-old male with extensive thromboembolism in the setting of asymptomatic COVID-19 infection and heterozygous factor V Leiden mutation with no additional thrombophilic risk factors.