Metabolismo de los esfingolípidos y su relación con las enfermedades cardiovasculares, renales y metabólicas / Sphingolipid metabolism and its relationship with cardiovascular, renal and metabolic diseases

Resumen Los esfingolípidos (esfingomielina, glucolípidos y gangliósidos) se localizan en las membranas celulares, el plasma y las lipoproteínas. En pacientes con enfermedades cardiovasculares, renales y metabólicas, el perfil de los esfingolípidos y sus metabolitos (ceramida, esfingosina y esfingosina-1-fosfato) se modifica, y estos cambios pueden explicar las alteraciones en algunas respuestas celulares, como la apoptosis. Además, se ha sugerido que la esfingosina y la esfingosina-1-fosfato previenen la COVID-19. En esta revisión también se mencionan brevemente las técnicas que permiten el estudio de los esfingolípidos y sus metabolitos.

Abstract Sphingolipids (sphingomyelin, glycolipids, gangliosides) are located in cell membranes, plasma, and lipoproteins. In patients with cardiovascular, renal, and metabolic diseases, the profile of sphingolipids and their metabolites (ceramide, sphingosine, and sphingosine-1-phosphate) is modified, and these changes may explain the alterations in some cellular responses such as apoptosis. Furthermore, sphingosine and sphingosine-1-phosphate have been suggested to prevent COVID-19. This review also briefly mentions the techniques that allow us to study sphingolipids and their metabolites.

The rs4783961 and rs708272 genetic variants of the CETP gene are associated with coronary artery disease, but not with restenosis after coronary stenting / Los polimorfismos rs4783961 y rs708272 del gen CETP son asociados con la enfermedad arterial coronaria y no con la restenosis tras el implante de un stent coronario

Abstract Objective: We evaluated whether cholesteryl ester transfer protein (CETP) gene polymorphisms are associated with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent. Methods: Two polymorphisms of the CETP gene [−971 A/G (rs4783961), and Taq1B A/G (rs708272)] were genotyped by 5'exonuclease TaqMan assays in 219 patients with CAD (66 patients with restenosis and 153 without restenosis) and 607 control individuals. Results: The distribution of polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under dominant model, the G allele of the Taq1B A/G polymorphism was associated with increased risk of CAD (odds ratio [OR] = 1.48, pCDom = 0.032). In the same way, under codominant, dominant, and additive models, the A allele of the −971 A/G polymorphisms was associated with an increased risk of developing CAD (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0.008, and OR = 1.39, pCAdd = 0.011, respectively). In addition, the linkage disequilibrium showed that the "AG" haplotype was associated with increased risk of developing CAD (OR = 1.28, p = 0.03). Conclusion: This study demonstrates that CETP Taq1B A/G and CETP −971 A/G polymorphisms are associated with an increased risk of developing CAD, but no association with restenosis was observed.

Resumen Objetivo: Evaluamos si los polimorfismos del gen CETP están asociados con la presencia de enfermedad arterial coronaria (EAC) y/o restenosis en pacientes con stent coronario. Métodos: En este estudio se genotiparon dos polimorfismos del gen CETP [−971 A/G (rs4783961) y Taq1B A/G (rs708272)] mediante ensayos de 5'exonucleasa TaqMan en 219 pacientes con EAC (66 pacientes con restenosis y 153 sin restenosis), y 607 individuos de control. Resultados: La distribución de polimorfismos fue similar en pacientes con y sin restenosis. Sin embargo, cuando se comparó todo el grupo de pacientes (con y sin restenosis) con controles sanos, bajo el modelo dominante el alelo G del polimorfismo Taq1B A/G se asocia con un mayor riesgo de EAC (OR = 1.48, pCDom = 0.032). De la misma manera, bajo los modelos co-dominante, dominante y aditivo, el alelo A de los polimorfismos −971 A/G se asocia con un mayor riesgo de desarrollar EAC (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0,008 y OR = 1.39, pCAdd = 0.011, respectivamente). Adicionalmente, el desequilibrio de ligamiento mostró que el haplotipo "AG" se asocia con un mayor riesgo de desarrollar EAC (OR = 1.28, p = 0.03). Conclusión: En resumen, este estudio demuestra que los polimorfismos CETP Taq1B A/G y CETP −971 A/G están asociados con un mayor riesgo de desarrollar CAD, pero no se observó asociación con restenosis.

HDL as Bidirectional Lipid Vectors: Time for New Paradigms.

The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.

The Role of P2X7 Purinergic Receptors in the Renal Inflammation Associated with Angiotensin II-induced Hypertension.

Purinergic receptors play a central role in the renal pathophysiology of angiotensin II-induced hypertension, since elevated ATP chronically activates P2X7 receptors in this model. The changes induced by the P2X antagonist Brilliant blue G (BBG) in glomerular hemodynamics and in tubulointerstitial inflammation resulting from angiotensin II infusion were studied. Rats received angiotensin II (435 ng·kg-1·min-1, 2 weeks) alone or in combination with BBG (50 mg/kg/day intraperitoneally). BBG did not modify hypertension (214.5 ± 1.4 vs. 212.7 ± 0.5 mmHg), but restored to near normal values afferent (7.03 ± 1.00 to 2.97 ± 0.27 dyn.s.cm-5) and efferent (2.62 ± 0.03 to 1.29 ± 0.09 dyn.s.cm-5) arteriolar resistances, glomerular plasma flow (79.23 ± 3.15 to 134.30 ± 1.11 nl/min), ultrafiltration coefficient (0.020 ± 0.002 to 0.036 ± 0.003 nl/min/mmHg) and single nephron glomerular filtration rate (22.28 ± 2.04 to 34.46 ± 1.54 nl/min). Angiotensin II induced overexpression of P2X7 receptors in renal tubular cells and in infiltrating T and B lymphocytes and macrophages. All inflammatory cells were increased by angiotensin II infusion and reduced by 20% to 50% (p < 0.05) by BBG administration. Increased IL-2, IL-6, TNFα, IL-1ß, IL-18 and overexpression of NLRP3 inflammasome were induced by angiotensin II and suppressed by BBG. These studies suggest that P2X7 receptor-mediated renal vasoconstriction, tubulointerstitial inflammation and activation of NLRP3 inflammasome are associated with angiotensin II-induced hypertension.

THE BRANCHED-CHAIN AMINO ACID TRANSAMINASE 1 -23C/G POLYMORPHISM CONFERS PROTECTION AGAINST ACUTE CORONARY SYNDROME.

BACKGROUND: Previous studies have shown an association between polymorphisms of the BAT1-NF-κB inhibitor-like-1 (NFKBIL1)-LTA genomic region and susceptibility to myocardial infarction and acute coronary syndrome (ACS). OBJECTIVE: The objective of the study was to study the role of three polymorphisms in the BAT1, NFKBIL1, and LTA genes on the susceptibility or protection against ACS; we included a group of cases-controls from Central Mexico. METHODS: The BAT1 rs2239527C/G, NFKBIL1 rs2071592T/A, and LTA rs1800683G/A polymorphisms were genotyped using a 5' TaqMan assay in a group of 625 patients with ACS and 617 healthy controls. RESULTS: Under a recessive model, the BAT1 -23C/G (rs2239527) polymorphism showed an association with protection against ACS (odds ratio = 0.56, and p-corrected = 0.019). In contrast, the genotype and allele frequencies of the NFKBIL1 rs2071592T/A and LTA rs1800683G/A polymorphisms were similar between ACS patients and controls and no association was identified. CONCLUSION: Our data suggest an association between the BAT1 -23C/G polymorphism and protection against ACS in Mexican patients.

The branched-chain amino acid transaminase 1 -23c/g polymorphism confers protection against acute coronary syndrome

ABSTRACT Background: Previous studies have shown an association between polymorphisms of the BAT1-NF-κB inhibitor-like-1 (NFKBIL1)-LTA genomic region and susceptibility to myocardial infarction and acute coronary syndrome (ACS). Objective: The objective of the study was to study the role of three polymorphisms in the BAT1, NFKBIL1, and LTA genes on the susceptibility or protection against ACS; we included a group of cases-controls from Central Mexico. Methods: The BAT1 rs2239527C/G, NFKBIL1 rs2071592T/A, and LTA rs1800683G/A polymorphisms were genotyped using a 5' TaqMan assay in a group of 625 patients with ACS and 617 healthy controls. Results: Under a recessive model, the BAT1 -23C/G (rs2239527) polymorphism showed an association with protection against ACS (odds ratio = 0.56, and p-corrected = 0.019). In contrast, the genotype and allele frequencies of the NFKBIL1 rs2071592T/A and LTA rs1800683G/A polymorphisms were similar between ACS patients and controls and no association was identified. Conclusion: Our data suggest an association between the BAT1 -23C/G polymorphism and protection against ACS in Mexican patients.

Atorvastatin and Fenofibrate Exert Opposite Effects on the Vascularization and Characteristics of Visceral Adipose Tissue in New Zealand White Rabbits.

Statins may precipitate the onset of type 2 diabetes (T2D) in high-risk patients. In contrast, only the subset of individuals with insulin resistance and/or diabetes receives cardiovascular benefits with fibrates. In this context, previous observations from our laboratory suggested that atorvastatin induced an increase in visceral adipose tissue (VAT), whereas fenofibrate had the opposite effects in rabbits. Therefore, we determined the mass, morphology, and vascularization of VAT in New Zealand white rabbits (n = 6/group) that received 0.33 or 2.6 mg/kg/d of atorvastatin or fenofibrate, respectively, during 2 months. As expected, the cholesterol from the atorvastatin group was lower after treatment, while triglycerides decreased in the fenofibrate group. The mass of VAT from the fenofibrate group was 46% lower compared to the controls, meanwhile atorvastatin was associated with a larger diameter of adipocytes (+65%) than that of the control and fenofibrate groups. Fibroblast growth factor 2 (FGF2) gene expression was lower in the fenofibrate group than in the control group (-54%). By contrast, vascular endothelial growth factor A (VEGF-A) gene expression in fenofibrate-treated rabbits was 110% higher than in the control group. In agreement with the gene expression, the marker of angiogenesis platelet endothelial cell adhesion molecule 1 was slightly but significantly higher (+10%) in rabbits treated with fenofibrate than in controls, as determined by immunohistochemistry. These results suggest that fenofibrate is associated with a favorable remodeling of VAT, that is, reduced mass and increased vascularization in normolipemic rabbits; in contrast, atorvastatin induced a nonfavorable remodeling of VAT. These results may be related to the cardiovascular benefits of fenofibrate and the increased risk of T2D in high-risk patients induced by atorvastatin.

Current Therapies Focused on High-Density Lipoproteins Associated with Cardiovascular Disease.

High-density lipoproteins (HDL) comprise a heterogeneous family of lipoprotein particles divided into subclasses that are determined by density, size and surface charge as well as protein composition. Epidemiological studies have suggested an inverse correlation between High-density lipoprotein-cholesterol (HDL-C) levels and the risk of cardiovascular diseases and atherosclerosis. HDLs promote reverse cholesterol transport (RCT) and have several atheroprotective functions such as anti-inflammation, anti-thrombosis, and anti-oxidation. HDLs are considered to be atheroprotective because they are associated in serum with paraoxonases (PONs) which protect HDL from oxidation. Polyphenol consumption reduces the risk of chronic diseases in humans. Polyphenols increase the binding of HDL to PON1, increasing the catalytic activity of PON1. This review summarizes the evidence currently available regarding pharmacological and alternative treatments aimed at improving the functionality of HDL-C. Information on the effectiveness of the treatments has contributed to the understanding of the molecular mechanisms that regulate plasma levels of HDL-C, thereby promoting the development of more effective treatment of cardiovascular diseases. For that purpose, Scopus and Medline databases were searched to identify the publications investigating the impact of current therapies focused on high-density lipoproteins.

Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes.

BACKGROUND AND AIMS: Research on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations. METHODS: In a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated. RESULTS: A significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42-54) to 45 (39-56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study. CONCLUSIONS: Short therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux.

Characterization of immortalized human dermal microvascular endothelial cells (HMEC-1) for the study of HDL functionality.

BACKGROUND: Primary cultures endothelial cells have been used as models of endothelial related diseases such atherosclerosis. Biological behavior of primary cultures is donor-dependent and data could not be easily reproducible; endothelial cell lines are emerging options, particularly, human dermal microvascular endothelial cells (HMEC-1), that should be validated to substitute primary cultures for the study of HDL functions. METHODS: Morphology, size and granularity of cells were assessed by phase contrast microscopy and flow cytometry of HMEC-1. The adhesion molecules, ICAM-1and VCAM-1 after TNF-α stimulation, and endothelial markers CD105 endoglin, as well as HDL receptor SR-BI were determined by flow cytometry. Internalization of HDL protein was demonstrated by confocal microscopy using HDL labeled with Alexa Fluor 488. HUVECs were used as reference to compared the characteristics with HMEC-1. RESULTS: HMEC-1 and HUVEC had similar morphologies, size and granularity. HMEC-1 expressed endothelial markers as HUVECs, as well as functional SR-B1 receptor since the cell line was able to internalize HDL particles. HMEC-1 effectively increased ICAM-1 and VCAM-1 expression after TNF-α stimulation. HUVECs showed more sensibility to TNF-α stimulus but the range of ICAM-1 and VCAM-1 expression was less homogeneous than in HMEC-1, probably due to biological variation of the former. Finally, the expression of adhesion molecules in HMEC-1 was attenuated by co-incubation with HDL. CONCLUSION: HMEC-1 possess characteristics of endothelial cells, similar to HUVECs, being a cell line suitable to evaluate the functionality of HDL vis-à-vis the endothelium.

Differential expression of osteopontin, and osteoprotegerin mRNA in epicardial adipose tissue between patients with severe coronary artery disease and aortic valvular stenosis: association with HDL subclasses.

BACKGROUND: Previous studies suggest a relationship of the epicardial adipose tissue (EAT) with progression and calcification of the atherosclerotic plaque; however, it is unknown if this tissue expresses genes that may participate on these processes and if the expression of these genes is regulated by high-density lipoprotein (HDL) subclasses. METHODS: To explore this possibility, we determined the mRNA expression by qPCR of a pro-calcifying gene (osteopontin (OPN)), and two anti-calcifying genes (osteoprotegerin (OPG) and osteonectin (ON)), in biopsies of EAT obtained from 15 patients with coronary artery disease (CAD) determined by angiography, and 15 patients with diagnostic of aortic valve stenosis but without CAD as control group. We determined the distribution and composition of HDL subclasses by electrophoresis and their statistical relationship with the gene expression in EAT. RESULTS: EAT from CAD patients showed a higher expression level of OPN and OPG than control group, whereas ON expression was similar between groups. Large HDL subclasses were cholesterol-poor in CAD patients as estimated by the cholesterol-to-phospholipid ratio. A linear regression model showed an independent association of OPN expression with HDL3a-cholesterol, and OPG expression with the relative proportion of HDL3b protein. Logistic analysis determined that OPN expression was positively associated with the presence of atherosclerotic plaque CONCLUSION: OPN, ON, and OPG genes are transcribed in EAT; to the exception of ON, the level of expression was different in CAD patients and control group, and correlated with some HDL subclasses, suggesting a new role of these lipoproteins.

The T>A (rs11646213) gene polymorphism of cadherin-13 (CDH13) gene is associated with decreased risk of developing hypertension in Mexican population.

Hypertension is a major public health problem affecting about 30% of the adult population and is associated with an increased risk of developing metabolic and cardiovascular disease. Recent reports have shown that the T-cadherin receptor characteristically expressed on endothelial and vascular smooth muscle cells is involved in hypertension. The aim of the present study was to evaluate the role of cadherin-13 (CDH13) gene polymorphisms as susceptibility markers for hypertension in Mexican population. Six CDH13 polymorphisms (rs11646213, rs11646411, rs6563943, rs3096277, rs3784990 and rs254340) were genotyped by 5' exonuclease TaqMan assays in a group of 644 hypertensive and 765 non-hypertensive individuals. Under co-dominant, recessive, and additive models, the CDH13 T>A (rs11646213) polymorphism was associated with decreased risk of developing hypertension when compared to non-hypertensive individuals (OR=0.61, 95% CI: 0.42-0.89, Pco-dom=0.019; OR=0.63, 95% CI: 0.46-0.87, Pres=0.005; OR=0.80, 95% CI: 0.66-0.96, Padd=0.016, respectively). All models were adjusted by gender, age, body index mass, type II diabetes mellitus, alcohol consumption, dyslipidemia and smoking habit. Linkage disequilibrium analysis showed one haplotype (TCACGG) with decreased frequency in hypertensive when compared to non-hypertensive individuals (OR=0.52, 95% CI: 0.33-0.82, P=0.0053). In summary, our data suggests that the CDH13 T>A (rs11646213) polymorphism is associated with decreased risk of developing hypertension in the Mexican population. In addition, it was possible to distinguish one haplotype associated with decreased risk and two for increased risk of develop hypertension.

PHACTR1 Gene Polymorphism Is Associated with Increased Risk of Developing Premature Coronary Artery Disease in Mexican Population.

Single-nucleotide polymorphisms (SNPs) in the protein phosphatase and actin regulator 1 gene (PHACTR1) have been associated with susceptibility to develop several diseases, including cardiovascular disease. The purpose of this study was to evaluate the role of two polymorphisms (rs2026458 and rs9349379) of the PHACTR1 gene in the susceptibility to the risk of developing premature coronary artery disease (CAD) in the Mexican population. The genotype analysis was performed using 5'exonuclease TaqMan genotyping assays in a group of 994 patients with premature CAD and 703 controls. A similar genotype distribution of rs2026458 was observed in both groups; however, under an additive model adjusted by age, body mass index, type 2 diabetes mellitus, smoking, dyslipidemia, and hypertension, the rs9349379 G allele was associated with a higher risk for developing premature CAD (odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.03-1.46, p-value (p) = 0.024). The two PHACTR1 polymorphisms were not in linkage disequilibrium. In summary, our results suggest that the PHACTR1 rs9349379 polymorphism plays an important role in the risk of developing premature CAD in the Mexican population.

Echocardiographic and Histologic Correlations in Patients with Severe Aortic Stenosis: Influence of Overweight and Obesity.

BACKGROUND: Severe aortic stenosis (AS), leads to pathological left ventricular remodeling that may worsen with concomitant overweight and obesity (OW/O). METHODS: We aimed to prospectively analyze the impact of OW/O on ventricular remodeling in severe AS, by evaluating the percentage of intraendomyocardial fibrosis (PIEF) and the percentage of infiltrating intraendocardial lipid vacuoles (PIELV) and its relationship to global longitudinal strain (GLS) in patients with OW/O. RESULTS: 44 patients with severe AS were included, 13 non-obese (29%) and 31 OW/O (71%), all of them with left ventricular ejection fraction ≥ 55%. GLS was evaluated with 2D speckle tracking. During valve replacement, an endocardial biopsy was obtained, where PIEF and PIELV were analyzed. Patients with higher PIEF and PIELV had greater body mass index (p < 0.0001) and worse GLS (p < 0.0053). A GLS cut-off point < -14% had a sensitivity of 75%, and a specificity of 92.8% to detect important PIEF (AUC: 0.928, 95% confidence interval: 0.798-1.00). On multivariate analysis, OW/O and PIELV were independently associated to the PIEF, and OW/O and PIEF were independently associated to GLS. A high correlation between the amount of PIELV and PIEF were found. CONCLUSION: Patients with severe AS and OW/O have greater PIEF and PIELV, suggesting more pathological remodeling. GLS is useful to detect subclinical myocardial injury and is potentially useful for endomyocardial fibrosis detection. The presence of higher PIELF may be a trigger factor for the development of intraendomyocardial fibrosis.

The interleukin-1ß-511 T>C (rs16944) gene polymorphism is associated with risk of developing silent myocardial ischemia in diabetic patients.

Silent myocardial ischemia (SMI) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. Considering the prominent role of IL-1ß, IL-1F10 and IL-1RN as regulators of the inflammatory process and vascular physiology, the aim of the present study was to analyze whether IL-1ß, IL-1F10 and IL-1RN single nucleotide polymorphisms (SNPs) are associated with SMI. One polymorphism was associated with risk of SMI. Under co-dominant, recessive and additive models, the IL-1ß-511 T>C polymorphism was associated with increased risk of SMI when compared to healthy controls (OR=4.68, 95%CI=2.21-9.92, pCCo-dom=0.0048; OR=3.97, 95%CI=1.97-7.99, pCRec=0.0024; OR=2.02, 95%CI=1.41-2.90, pCAdd=0.0024, respectively). All models were adjusted for gender, age and smoking. Linkage disequilibrium analysis showed four haplotypes (CTCC, CCTC, CCCT and CTCC) with increased frequency in SMI patients when compared to healthy controls (OR=2.53, 95%CI=1.47-4.36, pC=0.0009, OR=2.34, 95%CI=1.15-4.74, pC=0.02, OR=2.44, 95%CI=1.14-5.18, pC=0.02, OR=5.11, 95%CI=1.37-19.05, pC=0.01, respectively). In summary, our data suggest that the IL-1ß-511 T>C polymorphism plays an important role in the development of SMI in diabetic patients. In addition, in our study was possible to distinguish one protective and four risk haplotypes for development of SMI.

The C4280A (rs5705) gene polymorphism of the renin (REN) gene is associated with risk of developing coronary artery disease, but not with restenosis after coronary stenting.

The aim of the present study was to evaluate the role of AGT and REN gene polymorphisms as susceptibility markers for coronary artery disease (CAD) and/or restenosis after coronary stent placement in a group of Mexican patients. Five polymorphisms of the AGT (rs699, rs4762, rs5051, rs5049, rs5046) and two of the REN (rs5707, rs5705) genes were analyzed by 5' exonuclease TaqMan genotyping assays in 240 patients with CAD who underwent coronary artery stenting (76 with restenosis and 164 without restenosis). A group of 610 individuals without clinical and familial antecedents of cardiovascular diseases were included as controls. The results showed that the distribution of AGT and REN polymorphisms were similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under co-dominant, dominant, heterozygous and additive models, the REN A4280C (rs5705) polymorphism was associated with increased risk of CAD (OR=1.76, PCo-dom=0.006, OR=1.81, PDom=0.001, OR=1.75, PHet=0.003 and OR=1.59, PAdd=0.003, respectively). All models were adjusted for age, gender, diabetes, dyslipidemia, hypertension and smoking habit. The TC haplotype of the REN gene was associated with increased risk of CAD (OR=1.53, P=0.014). The data suggest that the REN C4280A (rs5705) polymorphism plays an important role in the risk of developing CAD with the highest risk for C allele, but do not support its role as a risk factor for developing restenosis after coronary stenting.

The ACE I/D polymorphism is associated with nitric oxide metabolite and blood pressure levels in healthy Mexican men / El polimorfismo I/D de la ECA se asocia con los niveles de metabolitos óxido nítrico y de presión arterial en hombres mexicanos sanos

The I/D insertion/deletion polymorphism of the angiotensin-converting enzyme has been related to hypertension. This polymorphism also seems to have gender related implications. Angiotensin II contributes to the production and release of oxygen reactive species that react with nitric oxide, inactivating its effects. Objective: To establish whether the ACE I/D polymorphism correlates with nitric oxide plasma metabolites in healthy men and women. Methods: Among 896 subjects between 18 and 30 years of age range, 138 fulfilled inclusion criteria. The polymorphism was identified by polymerase chain reaction, and blood nitric oxide metabolites were analyzed following the method described by Bryan. Results: Both systolic and diastolic arterial pressures were higher in men than in women (107/67 vs. 101/65 mmHg, p < 0.001). In terms of the ACE gene, there were differences in the concentration of nitric oxide metabolites in men with the I/D and D/D genotypes when compared to carriers of the I/I genotype (33.55 and 29.23 vs. 53.74 pmol/ml; p = <0.05), while there were no significant differences in women when compared by genotype. Men with the D/D genotype had higher systolic blood pressure than I/D carriers (111 vs. 104 mmHg, p < 0.05). We observed no arterial blood pressure differences in women when grouped by ACE genotype. Conclusions: The ACE D/D genotype was associated with nitric oxide metabolite levels and systolic blood pressure in clinically healthy men while it had no effect in women.

El polimorfismo inserción/deleción del gen de la enzima convertidora de la angiotensina (polimorfismo I/D de la ECA), se relaciona con hipertensión y sus efectos podrían estar asociados al género. La angiotensina II contribuye a la producción y liberación de especies reactivas de oxígeno, que reaccionan con el óxido nítrico (ON), inactivándolo. Objetivo: Conocer si existen diferencias en la concentración de metabolitos de ON en hombres y mujeres sanos que puedan estar influidas por el polimorfismo I/D de la ECA. Métodos: De 896 sujetos de entre 18 y 30 años, 138 cumplieron los criterios de inclusión. El polimorfismo fue identificado usando reacción en cadena de la polimerasa y los metabolitos de ON fueron analizados en sangre usando el método de Bryan. Resultados: Las presiones sistólica y diastólica fueron más elevadas en hombres que en mujeres (107/67 vs. 101/65 mmHg p < 0.001). En relación con el genotipo, existieron diferencias significativas en la concentración de metabolitos de ON en los hombres con genotipos I/D, D/D comparados con los portadores del genotipo I/I (33.55 y 29.23 vs. 53.74 pmol/ml, respectivamente; p = <0.05). No hubo diferencias significativas en las mujeres portadoras de los diferentes genotipos. Respecto a la presión arterial, los hombres con genotipo D/D presentaron mayor presión arterial sistólica que aquellos portadores de I/D (111 vs. 104 mmHg, p < 0.05). En las mujeres no se observaron diferencias significativas comparándolas por genotipo. Conclusiones: El genotipo D/D de la ECA está asociado con el nivel de metabolitos de ON en plasma y la presión arterial sistólica en hombres clínicamente sanos; esta asociación no se observa en las mujeres.

The variant rs8048002 T>C in intron 3 of the MHC2TA gene is associated with risk of developing acute coronary syndrome.

Recently, an intronic single nucleotide polymorphism (rs8048002) in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to several inflammatory diseases. The aim of the present study was to test for an association between this MHC2TA gene polymorphism and susceptibility to the risk of developing acute coronary syndromes (ACS) in a group of Mexicans patients. The single nucleotide polymorphism (rs8048002) of the MHC2TA gene was analyzed by 5' exonuclease TaqMan genotyping assays in a group of 452 patients with ACS and 456 healthy controls. The C allele and TC genotype were associated with risk of developing ACS (OR=4.55, pC=6×10(-4) and OR=4.41, pC=1.5×10(-3), respectively). Multiple logistic analysis was used for estimate risk between ACS patients and controls adjusted by cardiovascular risk factors (gender, age, hypertension, dyslipidemia, smoking, diabetes, body mass index and alcohol consumption). In this analysis, the TC+CC genotypes were significantly associated with increased risk of ACS as compared to TT genotype (OR=4.56, pC=0.004). In summary, our data suggest that the MHC2TA rs8048002 C>T gene polymorphism plays an important role in the risk of developing ACS.

Association of the suppressor of cytokine signaling 1 (SOCS1) gene polymorphisms with acute coronary syndrome in Mexican patients.

Recent studies provide evidence on the emerging role of the SOCS1 gene in the development and progression of atherosclerotic lesions. This gene encodes for the suppressor of the cytokine signaling-1 protein that interacts directly with the Janus kinases that are essential intracellular mediators of the immune cytokine action. The aim of this study was to test for associations between SOCS1 gene single nucleotide polymorphisms (SNPs) and the risk of developing acute coronary syndromes (ACS) in a group of Mexicans patients. Four SNPs [-3969 C>T (rs243327), -1656 G>A (rs243330), -820 G>T (rs33977706) and +1125 G>C (rs33932899)] of SOCS1 gene were determined for TaqMan genotyping assays in a group of 447 patients with ACS and 622 healthy controls. Under heterozygous model, the -3969 C>T (rs243327) SNP was associated with increased risk of ACS (OR=1.45, P(Het)=0.021). On the other hand, under co-dominant and heterozygous models, the -1656 G/A (rs243330) SNP was associated with increased risk of ACS (OR=1.47, P(Co-dom)=0.038 and OR=1.50, P(Het)=0.013, respectively). Moreover, under co-dominant, dominant, and heterozygous models, the -820T/G (rs33977706) SNP was associated with increased risk of ACS (OR=1.59, P(Co-dom)=0.03, OR=1.48, P(Dom)=0.028 and OR=1.61, P(Het)=0.01). Finally, under co-dominant and heterozygous models, the +1125 G/C (rs33932899) SNP was associated with increased risk of ACS (OR=1.54, P(Co-dom)=0.006, OR=1.58, P(Het)=0.012, respectively). Models were adjusted for gender, age, body index mass, dyslipidemia, alcohol consumption, and smoking. In summary, our data suggests that the four studied polymorphisms of the SOCS1 gene play an important role as susceptibility markers for developing ACS.

Early endothelial nitrosylation and increased abdominal adiposity in Wistar rats after long-term consumption of food fried in canola oil.

OBJECTIVE: The aim of this study was to establish whether the long-term consumption of reused canola oil contributes to the development of dyslipidemia, obesity, and endothelial function. METHODS: Canola oil was used for one frying cycle (1 FC) of corn flour dough or reused 10 times (10 FC). Rats received chow diet (control) or supplemented with 7% raw oil (RO), 1 FC or 10 FC oil (n = 10 per group). Food consumption, blood pressure (BP), and body weight plasma glucose, plasma lipids were monitored. Vascular reactivity was analyzed using aorta rings stimulated with phenylephrine and acetylcholine. Nitrotyrosine presence in aorta rings was analyzed by immunohistochemistry. RESULTS: After 10 wk of follow-up, visceral adipose tissue was significantly more abundant in 1 FC (7.4 ± 0.6 g) and 10 FC (8.8 ± 0.7 g) than the RO (5.0 ± 0.2 g; P = 0.05 versus 10 FC group) or control group (2.6 ± 0.3 g; P = 0.05 versus all groups). Despite similar plasma cholesterol, triglycerides, and BP among groups, a significantly reduced acetylcholine-induced vascular relaxation was observed in the three groups receiving the oil-supplemented diet (47.2% ± 3.6%, 27.2% ± 7.7%, and 25.9% ± 7.6% of relaxation, for the RO, 1 FC, and 10 FC, respectively; P < 0.05 for all versus 62.4% ± 9.7% of the control group). Endothelial dysfunction was concomitant with the presence of nitrotyrosine residues at a higher extent in the groups that received heated oils compared with the RO group. CONCLUSION: High canola oil intake over 10 wk was associated with increased adipose tissue and early endothelial dysfunction probably induced by peroxinitrite formation. Such deleterious effects were significantly potentiated when the consumed oil had been used repeatedly for frying.