RESUMEN
OBJECTIVE: Accumulation of cholesterol in foam cells of atheroma plaques depends on the balance between uptake and efflux of cholesterol. It may also depend on proteins surrounding lipid droplets, adipophilin, and perilipins. They favor triglyceride storage in adipocytes and could play a similar role for cholesterol in atheroma. METHODS AND RESULTS: We measured in human atheroma and nearby macroscopically intact tissue (MIT) the expression of perilipin, adipophilin, and regulatory factors of cholesterol metabolism. We identified perilipin A in human arterial wall. Its expression was largely increased in atheroma compared with MIT, and perilipin was present in macrophages and vascular smooth muscle cells. Adipophilin, ACAT1, and CD36 were also overexpressed in atheroma. mRNA levels of low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and SREBP-2 were unchanged. With respect to efflux of cholesterol, the mRNA levels of NCEH and ABCA-1 were unchanged, whereas CLA-1 mRNA was slightly higher in atheroma. Importantly, immunoblotting of ABCA-1 showed a dramatic decrease of ABCA1 protein, the key molecule of cholesterol efflux, in atheroma compared with MIT. CONCLUSIONS: We show the presence and induction of perilipin in atheroma. This overexpression and the coordinated modifications of expression of key regulatory factors for cholesterol metabolism could favor cholesterol accumulation.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Colesterol/metabolismo , Fosfoproteínas/genética , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Anciano , Animales , Arterias/metabolismo , Arterias/patología , Aterosclerosis/patología , Antígenos CD36/genética , Proteínas Portadoras , Células Cultivadas , Femenino , Células Espumosas/metabolismo , Células Espumosas/patología , Regulación de la Expresión Génica , Humanos , Leucocitos Mononucleares/citología , Masculino , Proteínas de la Membrana/genética , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Perilipina-1 , Perilipina-2 , Fosfoproteínas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Esterol O-Aciltransferasa/genéticaRESUMEN
OBJECTIVES: We have previously reported that 5-lipoxygenase-derived products, and particularly the cysteinyl leukotrienes (CysLTs), were involved in angiotensin II (Ang II)-induced contractions in isolated aortas from spontaneously hypertensive rats. DESIGN: The aim of this study was to assess the role of CysLTs in the vascular response to Ang II in an Ang II-dependent model of hypertension, the (mRen-2)27 transgenic rats (TGs). METHODS: Intact aortic rings from TG and normotensive Sprague-Dawley rats (SDs) were suspended in organ chambers for isometric tension development in response to Ang II. In addition, the release of CysLTs in response to Ang II (0.3 micromol/l) was measured by enzyme immunoassay. RESULTS: In isolated aortas from TG rats, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 micromol/l) or the CysLT1 receptor antagonist (MK571, 1 micromol/l) significantly (P < 0.05) reduced Ang II-induced contractions by 52 and 42%, respectively. In addition, Ang II induced a 2.6-fold increase in CysLT release (pg/mg dry weight tissue: 58.3 +/- 17.9 (Ang II, n = 7) versus 22.5 +/- 5.9 (basal, n = 7) P < 0.05), which was inhibited by the AT1 receptor antagonist losartan (1 micromol/l). In contrast, in aortas from SD rats, pretreatment with AA861 or MK571 did not alter Ang II-induced contraction and CysLT production remained unchanged after exposure to Ang II. CONCLUSION: These data suggest that CysLTs are involved in the contractile responses to Ang II in isolated aortas from TG but not from SD rats.