RAUL CAVALCANTE MARANHAO
Projetos de Pesquisa
Unidades Organizacionais
FBC, FCF - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Paclitaxel Delivered With Nanoparticles Inhibits Neointimal Formation and Local Inflammation in Experimental Chronic Allograft Vasculopathy(2014) PEPINELI, R.; SANTANA, A.; TIEME, A.; DEUS, D.; MARANHAO, R.; NORONHA, I.- Favorable effects of ezetimibe alone or in association with simvastatin on the removal from plasma of chylomicrons in coronary heart disease subjects(2014) MANGILI, Otavio Celeste; GAGLIARDI, Ana C. Moron; MANGILI, Leonardo Celeste; MESQUITA, Carlos H.; CESAR, Luiz A. Machado; TANAKA, Akira; SCHAEFER, Ernst J.; MARANHAO, Raul C.; SANTOS, Raul D.Objective: Reductions on the clearance from plasma of chylomicrons are associated with atherosclerosis. Statins improve the removal from plasma of chylomicrons in a dose dependent manner. There is controversy whether ezetimibe modifies the plasma clearance of chylomicrons. Effects of ezetimibe alone or in combination with simvastatin were compared with low and high dose of the latter, upon the kinetics of a chylomicron-like emulsion in coronary heart disease (CHD) patients. Methods: 25 CHD patients were randomized for treatment with ezetimibe 10 mg (group 1) or simvastatin 20 mg (group 2) with progression to ezetimibe + simvastatin 10/20 mg or simvastatin 80 mg, respectively. Kinetic studies were performed at baseline and after each treatment period of 6 weeks. The fractional catabolic rates (FCR) of the emulsion labeled with C-14-CE and H-3-TG, that represent respectively chylomicron remnant and triglyceride removal, were calculated. Comparisons were made by ANOVA. Results: The (CE)-C-14-FCR in group 1 were 0.005 +/- 0.004, 0.011 +/- 0.008 and 0.018 +/- 0.005 min(-1) and in group 2 were 0.004 +/- 0.003, 0.011 +/- 0.008 and 0.019 +/- 0.007 min(-1) respectively at baseline, after 6 and 12 weeks (p < 0.05 vs. baseline, and 6 vs. 12 weeks). The H-3-TG-FCR in group 1 were 0.017 +/- 0.011, 0.024 +/- 0.011 and 0.042 +/- 0.013 min(-1) and in group 2 were 0.016 +/- 0.009, 0.022 +/- 0.009 and 0.037 +/- 0.012 min(-1) at baseline, after 6 and 12 weeks (p < 0.05 vs. baseline, and 6 vs. 12 weeks). There were no differences between groups in time. Conclusion: Both treatments increased similarly the removal from plasma of chylomicron and remnants in CHD patients.
- What is new in familial hypercholesterolemia?(2014) SANTOS, Raul D.; MARANHAO, Raul C.Purpose of reviewThe purpose of this review is to describe advances in the diagnosis, cause, metabolism, risk factors for atherosclerosis, and treatment of familial hypercholesterolemia.Recent findingsHeterozygous familial hypercholesterolemia is almost four-fold more frequent than previously thought and is associated with 10-fold to 13-fold risk of cardiovascular disease comparing with normolipidemics. LDL receptor (LDLR) dysfunction and LDL-cholesterol (LDL-C) accumulation disturb the metabolism of other lipoprotein classes, such as chylomicrons and remnants and HDL. Next-generation sequencing can improve familial hypercholesterolemia molecular diagnosis due to its better performance and lower costs than usual techniques. Despite this, roughly 40% of familial hypercholesterolemia patients do not present mutations on the LDLR, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 genes. Many individuals with familial hypercholesterolemia phenotype have polygenic instead of monogenic cause of their elevated LDL-C concentrations. Individuals with familial hypercholesterolemia show elevated burden of subclinical atherosclerosis. The intensity of atherosclerosis burden is associated with the severity of LDLR mutation rather than maternal or paternal heritability. Newer-approved and on-development medications that reduce LDL-C hold promise for preventing cardiovascular disease in familial hypercholesterolemia.SummaryFamilial hypercholesterolemia is frequent and currently underdiagnosed and undertreated, but effective cascade screening programs and early and intensive LDL-C lowering can change this picture and the natural history of the disease.
conferenceObject LIPID TRANSFER TO HDL IN PATIENTS WITH CORONARY ARTERY DISEASE(2014) SPRANDEL, Mar lia O.; HUEB, Whady; CASELLA-FILHO, Antonio; SCUDELER, Thiago; REZENDE, Paulo; LIMA, Eduardo; SEGRE, Alexandre; CARVALHO, Ana; MARANHAO, Raul; KALIL-FILHO, RobertoconferenceObject IN BOTH GENDERS, HIGH RATE UNESTERIFIED CHOLESTEROL TRANSFER TO HDL IN THE PLASMA CAN BE PROTECTIVE AGAINST CORONARY ARTERY DISEASE(2014) SPRANDEL, M. C. O.; HUEB, W. A.; SEGRE, A. C.; LAVERDY, O. G.; LEITE-JUNIOR, A. C.; FREITAS, F. R.; KALIL-FILHO, R.; MARANHAO, R. C.- Human Paraoxonase-1 Activity Is Related to the Number of CD4+T-Cells and Is Restored by Antiretroviral Therapy in HIV-1-Infected Individuals(2014) MASELLI, Luciana Morganti Ferreira; CUNHA, Joel da; GUTIERREZ, Eliana Battaggia; MARANHAO, Raul Cavalcante; SPADA, Celso; BYDLOWSKI, Sergio PauloBackground. Paraoxonase-1 (PON1) activity is suggested to be altered in individuals infected with human immunodeficiency virus type-1 (HIV-1). We investigated PON1 activity in individuals receiving different regimens of highly active antiretroviral therapy (HAART). Methods. PON1 activity was evaluated in 91 HIV-1 seronegative and 624 HIV-1 infected individuals (115 were not undergoing therapy (ART-naive), and 509 were receiving HAART). HIV-1 infected individuals were treated with the following: efavirenz (EFV;n = 195) or nevirapine (NVP;n = 95) or lopinavir/ritonavir (LOP/r; n = 219). Serum levels of total cholesterol (TC), HDL, and low-density lipoprotein (LDL) fractions and the atherogenic indices (AI, TC : HDL, and LDL : HDL ratios) were determined. Results. PON1 activity (U/L) was lower in the ART-naive group compared with the other groups. PON1 activity correlated with CD4+ T-cell number of ART-naive group (r = 0, 121; P = 0, 014). The LOP/r group showed a reduction in HDL and an increase in AI (TC: HDL ratio) in comparison with other groups. Conclusion. PON1 activity was reduced in untreated individuals, but not in individuals receiving HAART. PON1 activity correlated with the number of CD4+ T-cells. The findings suggest that the activity of PON1 is associated with the immune status of HIV-1 infected individuals.
- Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice(2014) CONTENTE, Thais C.; KRETZER, Iara F.; FILIPPIN-MONTEIRO, Fabiola B.; MARIA, Durvanei A.; MARANHAO, Raul C.ObjectivesTo test the toxicity and antitumoral activity of the compound N-oleyl-daunorubicin (oDNR) with a cholesterol-rich nanoemulsion (LDE) formulation. MethodsLDE-oDNR was prepared by high-pressure homogenisation of lipid mixtures. B16F10 melanoma cells and NIH/3T3 fibroblasts were used for cytotoxicity tests. The maximum tolerated dose (MTD) of both commercial and LDE-oDNR was determined in mice, and melanoma-bearing mice were used for the antitumoral activity tests. Key findingsCC50 for LDE-oDNR and DNR in melanoma cells were 200m and 15m, respectively, but LDE-oDNR was less toxic against fibroblasts than DNR. MTD for LDE-oDNR was 65-fold higher than commercial DNR. In tumour-bearing mice, LDE-oDNR (7.5mol/kg) reduced tumour growth by 592%, whereas the reduction by DNR was only 23 +/- 2%. LDE-oDNR increased survival rates (P<0.05), which was not achieved by DNR treatment. The number of mice with metastasis was only 30% in LDE-oDNR-treated mice, compared with 82% under DNR treatment. By flow cytometry, there were 9% viable cells in tumours of animals treated with LDE-oDNR compared with 27% in DNR-treated animals. Less haematological toxicity was observed in LDE-oDNR-treated mice. ConclusionsCompared with DNR, LDE-oDNR improved tumour growth inhibition and survival rates with pronouncedly less toxicity, and thus may become a new tool for cancer treatment.
- Plasma kinetics of chylomicron-like emulsion and lipid transfers to high-density lipoprotein (HDL) in lacto-ovo vegetarian and in omnivorous subjects(2014) VINAGRE, Juliana C.; VINAGRE, Carmen C. G.; POZZI, Fernanda S.; ZACARI, Cristiane Z.; MARANHAO, Raul C.Previously, it was showed that vegan diet improves the metabolism of triglyceride-rich lipoproteins by increasing the plasma clearance of atherogenic remnants. The aim of the current study was to investigate this metabolism in lacto-ovo vegetarians whose diet is less strict, allowing the ingestion of eggs and milk. Transfer of lipids to HDL, an important step in HDL metabolism, was tested in vitro. Eighteen lacto-ovo vegetarians and 29 omnivorous subjects, all eutrophic and normolipidemic, were intravenously injected with triglyceride-rich emulsions labeled with C-14-cholesterol oleate and H-3-triolein. Fractional clearance rates (FCR, in min(-1)) were calculated from samples collected during 60 min. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids. LDL cholesterol was lower in vegetarians than in omnivores (2.1 +/- A 0.8 and 2.7 +/- A 0.7 mmol/L, respectively, p < 0.05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegetarians than in omnivores (0.016 +/- A 0.012, 0.003 +/- A 0.003, p < 0.01), whereas triglyceride FCR was equal. Cholesteryl ester transfer to HDL was lower in vegetarians than in omnivores (2.7 +/- A 0.6, 3.5 +/- A 1.5 %, p < 0.05), but free cholesterol, triglyceride and phospholipid transfers and HDL size were equal. Similarly to vegans, lacto-ovo vegetarian diet increases remnant removal, as indicated by cholesteryl oleate FCR, which may favor atherosclerosis prevention, and has the ability to change lipid transfer to HDL.
- Lipoproteína (a): Estrutura, Metabolismo, Fisiopatologia e Implicações Clínicas(2014) MARANHAO, Raul Cavalcante; CARVALHO, Priscila Oliveira; STRUNZ, Celia Cassaro; PILEGGI, FulvioThe chemical structure of lipoprotein (a) is similar to that of LDL, from which it differs due to the presence of apolipoprotein (a) bound to apo B100 via one disulfide bridge. Lipoprotein (a) is synthesized in the liver and its plasma concentration, which can be determined by use of monoclonal antibody-based methods, ranges from < 1 mg to > 1,000 mg/dL. Lipoprotein (a) levels over 20-30 mg/dL are associated with a two-fold risk of developing coronary artery disease. Usually, black subjects have higher lipoprotein (a) levels that, differently from Caucasians and Orientals, are not related to coronary artery disease. However, the risk of black subjects must be considered. Sex and age have little influence on lipoprotein (a) levels. Lipoprotein (a) homology with plasminogen might lead to interference with the fibrinolytic cascade, accounting for an atherogenic mechanism of that lipoprotein. Nevertheless, direct deposition of lipoprotein (a) on arterial wall is also a possible mechanism, lipoprotein (a) being more prone to oxidation than LDL. Most prospective studies have confirmed lipoprotein (a) as a predisposing factor to atherosclerosis. Statin treatment does not lower lipoprotein (a) levels, differently from niacin and ezetimibe, which tend to reduce lipoprotein (a), although confirmation of ezetimibe effects is pending. The reduction in lipoprotein (a) concentrations has not been demonstrated to reduce the risk for coronary artery disease. Whenever higher lipoprotein (a) concentrations are found, and in the absence of more effective and well-tolerated drugs, a more strict and vigorous control of the other coronary artery disease risk factors should be sought.
- HDL Metabolism and Atheroprotection: Predictive Value of Lipid Transfers(2014) MARANHAO, Raul C.; FREITAS, Fatima R.High-density lipoprotein (HDL) intravascular metabolism is complex, and the major HDL functions are esterification of cholesterol and reverse cholesterol transport, in which cholesterol from cells is excreted in bile. HDL has also several other antiatherogenic functions: antioxidative, vasodilatatory, anti-inflammatory, antiapoptotic, antithrombotic, and anti-infectious. Low HDL cholesterol is a major risk factor for cardiovascular disease (CVD) and high HDL cholesterol may favor the many protective abilities of HDL. However, aspects of HDL function can be independent of HDL cholesterol levels, including the efflux of cholesterol from cells to HDL. Some populations show low incidence of CVD despite their low HDL cholesterol. Lipid exchange between HDL and other lipoproteins and cells is fundamental in HDL metabolism and reverse cholesterol transport. By determining HDL composition, lipid transfers can also affect HDL functions that depend on proteins that anchor on HDL particle surface. Cholesteryl ester protein (CETP) and phospholipid transfer protein facilitate lipid transfers among lipoprotein classes, but the role of the lipid transfers and transfer proteins in atherosclerosis and other diseases is not well established. CETP has become a therapeutic target because CETP inhibitors increase HDL cholesterol, but to date the clinical trials failed to show benefits for the patients. Recently, we introduced a practical in vitro assay to evaluate the simultaneous transfer from a donor nanoemulsion to HDL of unesterified and esterified cholesterol, phospholipids, and triglycerides. Groups of subjects at different clinical, nutritional, and training conditions were tested, and among other findings, lower transfer ratios of unesterified cholesterol to HDL were predictors of the presence of CVD.