RESUMO
Characterization of allelic variants is relevant to demonstrate associations among genetic background and susceptibility to develop cardiovascular diseases, which are the main cause of death in Chile. Association of APOB, APOE, and MTHFR polymorphisms with higher lipid levels and the risk of developing hypertension and cardiovascular diseases have been described. Thus, the aim of this study was to assess genotype distribution and relative allelic frequency of ApoB rs693, ApoE rs7412, ApoE rs429358, MTHFR rs1801131, and MTHFR rs1801133 allelic variants and their effects on lipid profile in young healthy men and women from Northern Chile. A group of 193 healthy subjects were enrolled for this study. Genotyping of rs693 (APOB), rs7412 and rs429358 (APOE), and rs1801131 and rs1801133 (MTHFR) polymorphisms were performed by real time PCR. In addition, lipid profiles were determined and associated to genetic data. The genotype distribution was APOB rs693 (CC = 37%, CT = 41%, and TT = 22%), APOE rs7412/rs429358 (E4 = 0.06, E3 = 0.91, and E2 = 0.03), MTHFR rs1801131 (AA = 57%, AC = 30%, and CC = 13%), and MTHFR rs1801133 (CC = 20%, CT = 47%, and TT = 33%). The association of the genetic variants with plasma lipid levels showed that women, but not men, carrying APOB mutated allele (T) and Apo E4 allele presented lower values of total cholesterol when compared with C/C homozygous genotype or E3 allele, respectively (p < 0.05). In addition, a subgroup analysis revealed that ApoB C/C homozygous women exhibited higher values of HDL-C when compared with men carrying identical genotype (p < 0.01). On the other hand, women carrying E4 allele exhibited lower values of triglycerides when compared with male carrying identical genotype (p < 0.05). Finally, women carrying mutate allele (C) for MTHFR rs1801131 showed lower levels of triglycerides when compared with A/A homozygous genotype (p < 0.05) and lower levels of LDL-C for MTHFR rs1801133 in females carrying (T) allele when compared with males carrying identical genotype (p < 0.05). In summary, the present data showed that APOB, APOE, and MTHFR single nucleotide polymorphisms are associated to lipid levels in a gender-dependent manner among healthy subjects from Northern Chile, especially in women.
RESUMO
BACKGROUND: Identification and characterization of genetic variants and their effects on human health may allow to establish relationships between genetic background and susceptibility to developing cardiovascular diseases. LDLR and PCSK9 polymorphisms have been associated with higher lipid levels and risk of cardiovascular diseases. Thus, the main aim of this study was to evaluate genotype distribution and relative allelic frequency of LDLR rs5925 (1959C > T) and PCSK9 rs505151 (23968 A > G) genetic variants and their effects on lipid levels of healthy subjects from northern Chile. METHODS: A total of 178 healthy individuals were recruited for this study. The genotyping of rs5925 (LDLR) and rs505151 (PCSK9) polymorphisms was performed by PCR-RFLP and qPCR, respectively. In addition, glucose and lipid levels were determined and associated with the genetic data. RESULTS: Genotype distribution for LDLR rs5925 polymorphism was as follows: CC = 19%; CT = 53%; and TT = 28% (HWE: χ2 = 0.80; P = .37), and for PCSK9 rs505151 genetic variant was as follows: AA = 93%; AG = 7%; and GG = 0% (HWE: χ2 = 0.22; P = .64). The frequency of T (rs5925) and G (rs505151) mutated alleles was 0.55 and 0.03, respectively. Data showed that individuals carrying LDLR mutated allele (T) presented lower values of total cholesterol, triglycerides, and LDL-cholesterol when compared to CC homozygous genotype (P < .05). Subgroup analysis revealed that women carrying the PCSK9 mutated allele (G) exhibited higher values of total cholesterol, triglycerides, HDL-C, and LDL-C when compared to male group carrying the same genotype (P < .05). CONCLUSIONS: The effect of LDLR rs5925 and PCSK9 rs505151 gene polymorphisms on lipid levels is associated with gender among healthy subjects from northern Chile.
Assuntos
Predisposição Genética para Doença , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Adulto , Chile , Feminino , Frequência do Gene/genética , Humanos , Masculino , Adulto JovemRESUMO
Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The effect of short-term beta-adrenergic stimulation by isoproterenol on the activity of plasma, lung, and left ventricular (LV) angiotensin I-converting enzyme (ACE) activity and its association with the development of cardiac apoptosis was investigated. beta-Adrenergic stimulation for 24 hours produced an early increase only in the proapoptotic proteins bax and bcl-XS without changes in the levels of the antiapoptotic protein bcl-XL. The ratio between these bcl family proteins was indicative of apoptosis and correlated with an early and significant increase (300%) in DNA laddering. However, after 5 days of the beta-adrenergic stimulation, the ratio changed in favor of antiapoptotic proteins and correlated with the absence of DNA fragmentation. In addition, LV and plasma ACE activities increased markedly with isoproterenol over the study period up to 5 days. ACE activity also regulated expression of the antiapoptotic gene bcl-XL. The administration of perindopril (an ACE inhibitor) prevented the observed increase in bax and bcl-XS levels and attenuated (50% decrease, P<0.05) the effect of isoproterenol on DNA fragmentation. Thus, early and transient cardiac apoptosis triggered by the beta-adrenergic agonist isoproterenol is reversed in the presence of perindopril.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Apoptose/efeitos dos fármacos , Coração/efeitos dos fármacos , Miocárdio/citologia , Perindopril/farmacologia , Animais , Fragmentação do DNA , Isoproterenol/farmacologia , Pulmão/enzimologia , Masculino , Miocárdio/enzimologia , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/biossíntese , Proteína bcl-X/metabolismoRESUMO
Cells adapt to hyperosmotic conditions by several mechanisms, including accumulation of sorbitol via induction of the polyol pathway. Failure to adapt to osmotic stress can result in apoptotic cell death. In the present study, we assessed the role of aldose reductase, the key enzyme of the polyol pathway, in cardiac myocyte apoptosis. Hyperosmotic stress, elicited by exposure of cultured rat cardiac myocytes to the nonpermeant solutes sorbitol and mannitol, caused identical cell shrinkage and adaptive hexose uptake stimulation. In contrast, only sorbitol induced the polyol pathway and triggered stress pathways as well as apoptosis-related signaling events. Sorbitol resulted in activation of the extracellular signal-regulated kinase (ERK), p54 c-Jun N-terminal kinase (JNK), and protein kinase B. Furthermore, sorbitol treatment resulting in induction and activation of aldose reductase, decreased expression of the antiapoptotic protein Bcl-xL, increased DNA fragmentation, and glutathione depletion. Apoptosis was attenuated by aldose reductase inhibition with zopolrestat and also by glutathione replenishment with N-acetylcysteine. In conclusion, our data show that hypertonic shrinkage of cardiac myocytes alone is not sufficient to induce cardiac myocyte apoptosis. Hyperosmolarity-induced cell death is sensitive to the nature of the osmolyte and requires induction of aldose reductase as well as a decrease in intracellular glutathione levels.