RESUMO
Sex differences in disease susceptibility due to maternal programming have been reported. We previously observed that maternal smoking induced renal disease and neurological changes are restricted to males, while both male and female offspring develop metabolic disorders. We have also found that maternal L-carnitine supplementation during gestation and lactation can significantly improve glucose intolerance and hyperlipidaemia in male offspring. This study aimed to determine whether such beneficial effects can also occur in female offspring. Balb/c female mice were exposed to cigarette smoke (SE) 6 weeks prior to gestation, during gestation and lactation. A subgroup of the SE dams was given L-carnitine (1.5 mmol/L in drinking water) during gestation and lactation. Female offspring were studied at 20 days (weaning) and 13 weeks (adulthood). Maternal smoking increased liver weight (%) and blood glucose levels at 20 days, as well as glucose intolerance and plasma triglycerides levels at adulthood (P < .05). The hepatic lipid metabolic marker adipose triglyceride lipase was downregulated in the SE offspring at 20 days (P < .05). At 13 weeks, the hepatic pro-inflammatory markers IL-1ß and TNF-α mRNA expression were upregulated, while the anti-inflammatory marker IL-10 mRNA expression was downregulated in the SE offspring (P < .05). Liver fibrosis was apparent at 20 days and 13 weeks. Maternal L-carnitine supplementation either normalised or suppressed the detrimental effects induced by maternal smoke exposure (P < .05). We conclude that maternal L-carnitine supplementation improves metabolic parameters in the female offspring of SE dams.
Assuntos
Carnitina/farmacologia , Fumar Cigarros/efeitos adversos , Suplementos Nutricionais , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Exposição Materna/efeitos adversos , Animais , Biomarcadores/metabolismo , Feminino , Fibrose , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , GravidezRESUMO
OBJECTIVE: The purpose of this study was to investigate the ability of high-density lipoproteins (HDLs) to upregulate genes with the potential to protect against inflammation in endothelial cells. METHODS AND RESULTS: Human coronary artery endothelial cells (HCAECs) were exposed to reconstituted HDLs (rHDLs) for 16 hours before being activated with tumor necrosis factor-alpha (TNF-alpha) for 5 hours. rHDLs decreased vascular cell adhesion molecule-1 (VCAM-1) promoter activity by 75% (P<0.05), via the nuclear factor-kappa B (NF-kappaB) binding site. rHDLs suppressed the canonical NF-kappaB pathway and decreased many NF-kappaB target genes. Suppression of NF-kappaB and VCAM-1 expression by rHDLs or native HDLs was dependent on an increase in 3beta-hydroxysteroid-Delta 24 reductase (DHCR24) levels (P<0.05). The effect of HDLs on DHCR24 is dependent on SR-BI but not ABCAI or ABCGI. Silencing DHCR24 expression increased NF-kappaB (1.2-fold, P<0.05), VCAM-1 (30-fold, P<0.05), and NF-kappaB p50 (4-fold, P<0.05) and p65 subunits (150-fold, P<0.05). TNF-alpha activation of siDHCR24-treated cells increased expression of VCAM-1 (550-fold, P<0.001) and NF-kappaB (9-fold, P<0.001) that could no longer be suppressed by rHDLs. CONCLUSIONS: Results suggest that antiinflammatory effects of rHDLs are mediated partly through an upregulation of DHCR24. These findings raise the possibility of considering DHCR24 as a target for therapeutic modulation.
Assuntos
Apolipoproteína A-I/metabolismo , Arterite/prevenção & controle , Aterosclerose/prevenção & controle , Células Endoteliais/enzimologia , Lipoproteínas HDL/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Animais , Apolipoproteína A-I/administração & dosagem , Arterite/enzimologia , Arterite/etiologia , Arterite/genética , Aterosclerose/enzimologia , Aterosclerose/etiologia , Aterosclerose/genética , Células Cultivadas , Colesterol na Dieta , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Infusões Intravenosas , Lipoproteínas HDL/administração & dosagem , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Coelhos , Transfecção , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Cardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie.
