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AIMS: Considering the inconsistencies in the literature on the atorvastatin effect on blood pressure (BP), we performed these meta-analyses. METHODS AND RESULTS: Through a search of the Excerpta Medica Database (EMBASE), PubMed, and Web of Science databases, 1412 articles were identified, from which 33 randomized clinical trials (RCT) and 44 pre-clinical were selected. Populations from RCT were stratified according to baseline BP and lipid levels. We performed meta-analyses of the effect of atorvastatin on systolic (SBP), diastolic and mean BP; heart rate (HR); HR variability, and baroreflex. Atorvastatin reduced SBP in the overall population (P = 0.05 vs. placebo; P = 0.03 vs. baseline), in normotensive and hyperlipidaemic (P = 0.04 vs. placebo; P = 0.0001 vs. baseline) and in hypertensive and hyperlipidaemic (P = 0.02 vs. placebo; P = 0.008 vs. baseline) individuals in parallel RCT, but it did not affect SBP in normotensive and normolipidaemic individuals (P = 0.51 vs. placebo; P = 0.4 vs. baseline). Although an effect of atorvastatin was detected in hyperlipidaemic individuals, the meta-regression coefficient for the association of low density lipoprotein (LDL)-cholesterol reduction with SBP reduction in the overall population demonstrated that SBP reduction is not dependent on the changes in LDL-cholesterol. A meta-analysis of preclinical reports demonstrated that SBP was reduced in atorvastatin-treated hypertensive and normolipidaemic rats (spontaneously hypertensive rats: P < 0.00001), but not in normotensive and normolipidaemic rats (control rats: P = 0.97). Atorvastatin also reduced the HR in spontaneously hypertensive rat. CONCLUSION: Atorvastatin lowers BP independent of LDL-cholesterol levels. Additional studies are needed to estimate the involvement of the autonomic nervous system in the BP-lowering effect of atorvastatin.
Asunto(s)
Hipertensión , Humanos , Ratas , Animales , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Presión Sanguínea , Frecuencia Cardíaca , Hipertensión/tratamiento farmacológico , ColesterolRESUMEN
Mitochondria possess a Ca2+ transport system composed of separate Ca2+ influx and efflux pathways. Intramitochondrial Ca2+ concentrations regulate oxidative phosphorylation, required for cell function and survival, and mitochondrial redox balance, that participates in a myriad of signaling and damaging pathways. The interaction between Ca2+ accumulation and redox imbalance regulates opening and closing of a highly regulated inner membrane pore, the membrane permeability transition pore (PTP). In this review, we discuss the regulation of the PTP by mitochondrial oxidants, reactive nitrogen species, and the interactions between these species and other PTP inducers. In addition, we discuss the involvement of mitochondrial redox imbalance and PTP in metabolic conditions such as atherogenesis, diabetes, obesity and in mtDNA stability.
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Aterosclerosis/metabolismo , Calcio/metabolismo , Diabetes Mellitus/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Obesidad/metabolismo , Animales , Aterosclerosis/genética , Aterosclerosis/patología , Cationes Bivalentes , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Humanos , Transporte Iónico , Proteínas de Transporte de Membrana Mitocondrial/genética , Membranas Mitocondriales/metabolismo , Obesidad/genética , Obesidad/patología , Oxidación-Reducción , Fosforilación Oxidativa , Permeabilidad , Especies de Nitrógeno Reactivo/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Hypertriglyceridemia is a common type of dyslipidemia found in obesity. However, it is not established whether primary hyperlipidemia can predispose to obesity. Evidences have suggested that proteins primarily related to plasma lipoprotein transport, such as apolipoprotein (apo) CIII and E, may significantly affect the process of body fat accumulation. We have previously observed an increased adiposity in response to a high fat diet (HFD) in mice overexpressing apoCIII. Here, we examined the potential mechanisms involved in this exacerbated response of apoCIII mice to the HFD. METHODS: We measured body energy balance, tissue capacity to store exogenous lipids, lipogenesis and lipolysis rates in non-transgenic and apoCIII overexpressing mice fed a HFD during two months. RESULTS: Food intake, fat excretion and whole body CO2 production were similar in both groups. However, the adipose tissue mass (45 %) and leptin plasma levels (2-fold) were significantly greater in apoCIII mice. Lipogenesis rates were similar, while exogenous lipid retention was increased in perigonadal (2-fold) and brown adipose tissues (40 %) of apoCIII mice. In addition, adipocyte basal lipolysis (55 %) and in vivo lipolysis index (30 %) were significantly decreased in apoCIII mice. A fat tolerance test evidenced delayed plasma triglyceride clearance and greater transient availability of non-esterified fatty acids (NEFA) during the post-prandial state in the apoCIII mice plasma. Thus, apoCIII overexpression resulted in increased NEFA availability to adipose uptake and decreased adipocyte lipolysis, favoring lipid enlargement of adipose depots. CONCLUSION: We propose that plasma apoCIII levels represent a new risk factor for diet-induced obesity.
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Fatty-acid-induced endoplasmic reticulum stress has been recently described as a novel mechanism involved in the genesis of atherosclerosis. Here we show that statins, a class of drug widely employed in the clinical management of hypercholesterolemia, reduces lipid-induced macrophage endoplasmic reticulum stress in an isolated cell system and in LDL receptor knockout mice. Given the importance of endoplasmic reticulum stress as an inducer of inflammation, we suspect that the novel mechanism of action herein described for statins may play a major role on its beneficial effects in the prevention of cardiovascular disease.
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Aterosclerosis/tratamiento farmacológico , Retículo Endoplásmico/efectos de los fármacos , Ácidos Grasos/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Macrófagos/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Animales , Antígenos de Diferenciación/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Línea Celular , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Fosforilación , Pravastatina/farmacología , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de Transcripción del Factor Regulador X , Simvastatina/farmacología , Factores de Transcripción/metabolismo , eIF-2 Quinasa/metabolismoRESUMEN
OBJECTIVES: Experimental and in vitro evidences have established that reactive oxygen species (ROS) generated by vascular wall cells play a key role in atherogenesis. Here, we evaluated the rate of ROS generation by resting peripheral monocytes in naive hyperlipidemic subjects. DESIGN AND METHODS: Primary hypercholesterolemic, combined hyperlipidemic, and normolipidemic individuals were studied. ROS generation and the mitochondrial electrical transmembrane potential were estimated by flow cytometry. Plasma oxidized (ox) LDL levels and lipid profile were measured by ELISA and enzymatic colorimetric methods. RESULTS: Both hyperlipidemic groups presented significantly higher rates of monocyte ROS generation and elevated plasma levels of ox-LDL. Combined hyperlipidemic subjects presented increased levels of small dense LDL and insulin. Significant positive correlations between monocyte ROS generation and ox-LDL concentrations were found in pooled data. CONCLUSIONS: These data provide evidence that ROS production by circulating monocytes from hyperlipidemic subjects may contribute to the systemic oxidative stress and possibly to atherogenesis.