RESUMEN
Atherosclerosis is a disease in which atheromatous plaques develop inside arteries, leading to reduced or obstructed blood flow that in turn may cause stroke and heart attack. Rose hip is the fruit of plants of the genus Rosa, belonging to the Rosaceae family, and it is rich in antioxidants with high amounts of ascorbic acid and phenolic compounds. Several studies have shown that fruits, seeds and roots of these plants exert antidiabetic, antiobesity and cholesterol-lowering effects in rodents as well as humans. The aim of this study was to elucidate the mechanisms by which rose hip lowers plasma cholesterol and to evaluate its effects on atherosclerotic plaque formation. ApoE-null mice were fed either an HFD (CTR) or HFD with rose hip supplementation (RH) for 24 weeks. At the end of the study, we found that blood pressure and atherosclerotic plaques, together with oxidized LDL, total cholesterol and fibrinogen levels were markedly reduced in the RH group. Fecal cholesterol content, liver expression of Ldlr and selected reverse cholesterol transport (RCT) genes such as Abca1, Abcg1 and Scarb1 were significantly increased upon RH feeding. In the aorta, the scavenger receptor Cd36 and the proinflammatory Il1ß genes were markedly down-regulated compared to the CTR mice. Finally, we found that RH increased nitric oxide-mediated dilation of the caudal artery. Taken together, these results suggest that rose hip is a suitable dietary supplement for preventing atherosclerotic plaques formation by modulating systemic blood pressure and the expression of RCT and inflammatory genes.
Asunto(s)
Antioxidantes/farmacología , Aterosclerosis/tratamiento farmacológico , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Rosa/química , Animales , Antioxidantes/análisis , Aorta/efectos de los fármacos , Aorta/metabolismo , Biomarcadores/sangre , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Colesterol/sangre , Femenino , Fibrinógeno/metabolismo , Frutas/química , Insulina/sangre , Lipoproteínas LDL/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Noqueados para ApoE , Extractos Vegetales/análisis , Placa Aterosclerótica/tratamiento farmacológico , Vasodilatación/efectos de los fármacosRESUMEN
Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof-of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis.
Asunto(s)
Caveolina 1/metabolismo , Proliferación Celular , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Poliaminas/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Animales , Western Blotting , Proteínas de Unión al Calcio/metabolismo , Arterias Carótidas/metabolismo , Arterias Carótidas/cirugía , Caveolina 1/genética , Movimiento Celular , Células Cultivadas , ADN/biosíntesis , Expresión Génica , Inmunohistoquímica , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Ornitina Descarboxilasa/genética , Ornitina Descarboxilasa/metabolismo , Poliaminas/farmacocinética , Poliaminas/farmacología , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , CalponinasRESUMEN
The hypothalamus is the main appetite-regulating center in the brain receiving peripheral signals regarding the metabolic status of the body. Pancreatic procolipase has recently been identified in rat hypothalamus. Procolipase is known mainly for its actions in the intestine where it is cleaved to colipase, an enzyme required for the maintenance of pancreatic lipase activity, and enterostatin, a peptide involved in appetite regulation through the gut-brain axis. Colipase is able to increase the activity of pancreatic lipase-related protein-2 (PLRP2), a lipase also expressed in extra-pancreatic tissues. This study was performed to elucidate if PLRP2, in addition to colipase, is expressed in the hypothalamus and if the mRNAs of colipase and PLRP2 respond to metabolic challenges such as fasting, high-fat feeding or feeding sugar solutions. RNA from rat hypothalamus was extracted and subjected to RT-PCR. For quantitative mRNA analysis of hypothalamic tissue from the different metabolic situations real-time RT-PCR was used. We found PLRP2 and colipase mRNA to be expressed in the hypothalamus. An overnight fast resulted in down-regulated colipase (3-fold) and PLRP2 (7-fold) mRNA compared to freely fed rats. Conversely, high-fat feeding resulted in up-regulated colipase and PLRP2 mRNA (1.3-fold and 1.8-fold, respectively) compared to standard chow-fed rats. A similar up-regulation in mRNA expression was observed after offering sugar solutions. In conclusion, PLRP2 mRNA is expressed in the rat hypothalamus and both procolipase and PLRP-2 mRNA are down-regulated during fasting and up-regulated during conditions of metabolic excess, suggesting an involvement in signaling energy availability.