Hyperlipidemias: Rodriguez C

Alcudia JF, Martinez-Gonzalez J, Guadall A, Gonzalez-Diez M, Badimon L, Rodriguez C. · Centro de Investigacion Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, c/Antoni Ma Claret 167, 08025 Barcelona, Spain. · Front Biosci. · Pubmed #17981747 No free full text.

Abstract: Lysyl oxidase (LOX) plays a pivotal role in extracellular matrix (ECM) maturation. Furthermore, novel biological functions has been ascribed to LOX, among them cell differentiation, migration, transformation and regulation of gene expression. In this context, it has been suggested that abnormalities of LOX expression could underlie the development of multiple pathological processes including cardiovascular diseases. LOX seems to be crucial in the preservation of endothelial barrier function. In fact, accumulating evidences suggest a role of this enzyme in atherogenesis and endothelial dysfunction triggered by atherosclerotic risk factors and pro-inflammatory cytokines. Indeed, cytokines such as tumour necrosis factor-alpha (TNF-alpha) modulate vascular LOX expression. This cytokine decreases LOX expression and activity in endothelial cells through a transcriptional mechanism that involves TNF receptor-2 and protein kinase C activation. Interestingly, in vivo studies reveal that TNF-alpha causes a down-regulation of vascular LOX expression. Thus, LOX down-regulation seems to be associated to the endothelial dysfunction elicited by multiple pathological factors. LOX rises as a promising target gene for the development of therapeutic strategies in the treatment of cardiovascular diseases.

Cohn JS, Tremblay M, Batal R, Jacques H, Veilleux L, Rodriguez C, Barrett PH, Dubreuil D, Roy M, Bernier L, Mamer O, Davignon J. · Hyperlipidemia and Atherosclerosis Research Group, Montréal, Québec, Canada. · J Lipid Res. · Pubmed #12235178 links to  free full text

Abstract: Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 +/- 0.9 to 4.3 +/- 0.2 mg/dl (-38 +/- 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 +/- 0.8 vs. 1.7 +/- 0.2 mg/dl; -42 +/- 11%) and IDL/LDL apoE (1.9 +/- 0.3 vs. 0.8 +/- 0.1 mg/dl; -57 +/- 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 +/- 0.39 to 3.04 +/- 0.51 mg/kg/day (-34 +/- 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 +/- 0.67 to 2.26 +/- 0.42 mg/kg/day (-36 +/- 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.

Mabile L, Piolot A, Boulet L, Fortin LJ, Doyle N, Rodriguez C, Davignon J, Blache D, Lussier-Cacan S. · Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Quebec, Canada. · Am J Clin Nutr. · Pubmed #11566642 links to  free full text

Abstract: BACKGROUND: The important triacylglycerol-lowering capacity of n-3 fatty acids is counterbalanced by their inherent sensitivity to oxidation. Inconsistent results about the latter have been reported in hypertriglyceridemic individuals. After incorporation into cell membranes, n-3 fatty acids may alter membrane-related functions. In view of the distinct composition of hypertriglyceridemic membranes and the prooxidant status in this condition, it can be surmised that cell enrichment with the oxidizable n-3 fatty acids will be associated with an increased hemolytic process. OBJECTIVE: We sought to evaluate the effect of fish oil consumption on n-3 fatty acid incorporation into erythrocyte membranes and subsequent ex vivo oxidative-stress-induced hemolysis in normotriglyceridemic and hypertriglyceridemic subjects. DESIGN: Sixteen normotriglyceridemic and 12 hypertriglyceridemic subjects were given 6 g fish oil/d for 8 wk. Blood samples were collected before and 4 and 8 wk after treatment. Resistance to 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced hemolysis was assayed in fresh erythrocyte suspensions, and erythrocyte samples were stored at -70 degrees C for later analysis of cholesterol, hemoglobin, fatty acids, vitamin E, and glutathione peroxidase activity. RESULTS: Fish oil supplementation induced n-3 fatty acid incorporation in normotriglyceridemic and hypertriglyceridemic erythrocyte membranes without decreasing their resistance to AAPH. n-3 Fatty acids significantly protected normotriglyceridemic but not hypertriglyceridemic erythrocytes against hemolysis. In normotriglyceridemic subjects only, the higher resistance to hemolysis correlated with changes in cell vitamin E. CONCLUSION: Although they exhibit a high susceptibility to oxidation, n-3 fatty acids may preserve membrane integrity and represent an added benefit in the treatment of hypertriglyceridemic patients.

Cohn JS, Tremblay M, Batal R, Jacques H, Rodriguez C, Steiner G, Mamer O, Davignon J. · Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Que., Canada H2W1R7. · Atherosclerosis. · Pubmed #15488876 No free full text.

Abstract: Apolipoprotein (apo) C-III plays an important role in regulating plasma triglyceride (TG) metabolism. In order to further investigate the plasma metabolism of apoC-III in hypertriglyceridemic subjects, we have studied the plasma kinetics of VLDL apoC-III, HDL apoC-III and total plasma apoC-III with a primed constant intravenous infusion of deuterated leucine in a group of male patients with mixed hyperlipidemia (type IIb hyperlipoproteinemia, HLP, n=6) and in a group with type III HLP (n=6). Compared to normolipidemic control subjects (n=5), patients with type IIb and type III HLP had significantly higher levels of plasma TG (0.89 +/- 0.15 mmol/l vs 2.56 +/- 0.40 mmol/l vs 8.76 +/- 1.39 mmol/l, respectively, P <0.01), plasma apoC-III (9.5 +/- 0.8 mg/dl vs 20.8 +/- 2.5 mg/dl vs 41.7 +/- 5.6 mg/dl, P <0.01) and VLDL apoC-III (3.6 +/- 0.8 mg/dl vs 14.6 +/- 2.2 mg/dl vs 35.4 +/- 5.1 mg/dl, P <0.01). VLDL apoC-III production rates were significantly elevated in type IIb and type III patients (1.35 +/- 0.23 mg kg(-1) day(-1) vs 3.53 +/- 0.43 mg kg(-1) day(-1) vs 5.60 +/- 0.78 mg kg(-1) day(-1), P <0.01), as were total plasma apoC-III production rates (1.80 +/- 0.22 mg kg(-1) day(-1) vs 4.16 +/- 0.44 mg kg(-1) day(-1) vs 7.26 +/- 0.74 mg kg(-1) day(-1), P <0.01). VLDL apoC-III but not total plasma apoC-III fractional catabolic rates were reduced in type IIb and type III patients. Together with our previous results showing an increase of apoC-III production in patients with type IV HLP, and in overweight subjects with reduced insulin sensitivity, our data suggest that increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia.

Rodriguez C, Raposo B, Martínez-González J, Llorente-Cortés V, Vilahur G, Badimon L. · Cardiovascular Research Center, ICCC-CSIC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Cardiovasc Res. · Pubmed #12667960 links to  free full text

Abstract: BACKGROUND: Plasma low density lipoproteins (LDL) play a key role in the pathogenesis of atherosclerosis. LDL modify gene expression in vascular cells leading to disturbances in the functional state of the vessel wall. METHODS: Expression levels of C-4 sterol methyl oxidase gene (ERG25), sterol regulatory element binding protein (SREBP)-1 and -2 were evaluated in porcine aortic endothelial cells (PAEC), porcine and human smooth muscle cells (SMC) and in the vascular wall from normolipemic and hyperlipemic pigs by RT-PCR. SREBP-1 protein levels were assessed by Western blot and SREBP-SRE binding by EMSA. SREBP-2 was overexpressed by transient transfection with lipofectin. RESULTS: We have identified expression of the ERG25 in vascular cells and analyzed its regulation by LDL. ERG25, an enzyme involved in cholesterol biosynthesis, is expressed in vascular endothelial and SMC from porcine and human origin and is downregulated by LDL in a time- and dose-dependent manner. Downregulation of ERG25 by LDL was abolished by an inhibitor of neutral cysteine proteases (N-acetyl-leucyl-leucyl-norleucinal) that abrogates SREBP catabolism. LDL downregulated SREBP-2 mRNA levels but not SREBP-1 expression in these cells and both ERG25 and SREBP-2 gene expression was significantly decreased in the vascular wall of diet-induced hypercholesterolemic swine. Finally, in cell transfection experiments SREBP-2 overexpression blocks ERG25 downregulation caused by LDL. CONCLUSIONS: Our results indicate that LDL modulate ERG25 expression in the vascular wall and suggest the involvement of SREBP-2 in this mechanism.

Cohn JS, Tremblay M, Batal R, Jacques H, Veilleux L, Rodriguez C, Bernier L, Mamer O, Davignon J. · Hyperlipidemia and Atherosclerosis Research Group, Montréal, Québec, Canada. · J Lipid Res. · Pubmed #12364552 links to  free full text

Abstract: ApoC-I has several different lipid-regulating functions including, inhibition of receptor-mediated uptake of plasma triglyceride-rich lipoproteins, inhibition of cholesteryl ester transfer activity, and mediation of tissue fatty acid uptake. Since little is known about the rate of production and catabolism of plasma apoC-I in humans, the present study was undertaken to determine the plasma kinetics of VLDL and HDL apoC-I using a primed constant (12 h) intravenous infusion of deuterium-labeled leucine. Data were obtained for 14 subjects: normolipidemics (NL, n = 4), hypertriglyceridemics (HTG, n = 4) and combined hyperlipidemics (CHL, n = 6). Plasma VLDL triglyceride (TG) levels were 0.59 +/- 0.03, 4.32 +/- 0.77 (P < 0.01 vs. NL), and 2.20 +/- 0.39 mmol/l (P < 0.01 vs. NL), and plasma LDL cholesterol (LDL-C) levels were 2.34 +/- 0.22, 2.48 +/- 0.26, and 5.35 +/- 0.48 mmol/l (P < 0.01 vs. NL), respectively. HTG and CHL had significantly (P < 0.05) increased levels of total plasma apoC-I (12.5 +/- 1.2 and 12.4 +/- 1.3 mg/dl, respectively) versus NL (7.9 +/- 0.6 mg/dl), due to significantly (P < 0.01) elevated levels of VLDL apoC-I (5.8 +/- 0.8 and 4.5 +/- 0.8 vs. 0.3 +/- 0.1 mg/dl). HTG and CHL also had increased rates of VLDL apoC-I transport (i.e., production) versus NL: 2.29 +/- 0.34 and 3.04 +/- 0.53 versus 0.24 +/- 0.11 mg/kg.day (P < 0.01), with no significant change in VLDL apoC-I residence times (RT): 1.16 +/- 0.12 versus 0.69 +/- 0.06 versus 0.74 +/- 0.17. Although HDL apoC-I concentrations were not significantly lower in HTG and CHL versus NL, HDL apoC-I rates of transport were inversely related to plasma and VLDL-TG levels (r = -0.63 and -0.62, respectively, P < 0.05). Our results demonstrate that increased levels of plasma and VLDL apoC-I in hypertriglyceridemic subjects (with or without elevated LDL-C levels) are associated with increased levels of plasma VLDL apoC-I production.