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Background: The efflux of cellular cholesterol mediated by apolipoprotein (apo)A-I and ATP-binding cassette transporter A1 (ABCA1) is a major pathway of reverse cholesterol transport. We investigated the effect of aspirin on this process. Methods: The expression levels of ABCA1 in RAW264.7 cells were determined using reverse transcription polymerase chain reaction and Western blot analysis. 3H-cholesterol efflux was measured by scintillation counting. Results: 0.5 mmol/l aspirin increased apoA-I-mediated cholesterol efflux and increased the expression of ABCA1. By increasing the dose of aspirin higher than 0.5 mmol/l, ABCA1 expression and function were significantly decreased. In cells transfected with a specific peroxisome proliferator-activated receptor (PPAR)-α small interfering RNA, the induction of ABCA1 expression and apoA-I-mediated 3H-cholesterol efflux by aspirin were substantially suppressed. Conclusions: The data demonstrate that low-dose aspirin increases ABCA1 expression via a PPAR-α-dependent mechanism and increases apoA-I-mediated cholesterol efflux. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Organic nitrates act as vasodilators and have long been used for treatment of cardiovascular diseases. However, the therapeutic effect of nitrates is limited by induction of nitrate tolerance which is associated with endothelial dysfunction and enhanced vasoconstriction. Multiple mechanisms cause nitrate tolerance including alterations in gene expression. To identify genes whose expression is altered due to chronic treatment with nitroglycerin (NTG), nitrate-tolerant rats were made by infusion of NTG for 3 days (10 μg/kg/min) using an osmotic minipump. We constructed a PCR-selected cDNA subtracted library from NTG-treated and vehicle-treated rat aortas. Screening of ∼500 clones in the subtracted library showed that four genes were regulated by NTG treatment. Specifically, mRNA levels of β-globin, tropoelastin, gelsolin and a small G protein were confirmed to be upregulated consistently by NTG treatment. These identified genes may play important roles in the development of nitrate tolerance and represent promising candidates to understand the mechanisms of nitrate tolerance and endothelial dysfunction in the vasculature.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported that disturbance of endogenous circadian rhythms enhances the chance of hypertension and suggested that circadian clock genes could have a crucial function in the onset of the disease. This case-control study was aimed to investigate the association of the mRNA expression of aryl hydrocarbon receptor nuclear translocator like (Arntl), clock circadian regulator (Clock), and period circadian regulators 1 and 2 (Per1 and Per2) with hypertension and blood pressure levels. Methods: A total of 172 subjects were recruited in this study, including 86 hypertension and 86 nonhypertension controls. The mRNA expression levels in peripheral blood mononuclear cells were determined by real-time quantitative polymerase chain reaction. The differences in Arntl, Clock, Per1, and Per2 mRNA expression were compared between the 2 groups, and the relationship between mRNA expression and cardiometabolic risk profiles was also assessed. Results: We found that the mRNA expression of Arntl was downregulated in the hypertension cases compared with controls in women (1.10 [0.66, 1.71] vs. 1.30 [0.99, 2.06], p = 0.031). There was a significant negative correlation between the Arntl mRNA expression and SBP (r = −0.301, p = 0.004) and DBP (r = −0.222, p = 0.034) in women. In men, a negative correlation between the Per1 mRNA expression and SBP (r = −0.247, p = 0.026) was found. Conclusions: The Arntl mRNA expression may play an important role in progression of hypertension in women. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has suggested that differentiation of adventitial fibroblasts (AFs) to myofibroblasts plays an important role in arterial remodeling. The molecular mechanisms by which myofibroblast formation is regulated still remain largely unknown. This study aimed to evaluate the role of cyclic nucleotide phosphodiesterase 1A (PDE1A) in the formation of adventitial myofibroblasts induced by transforming growth factor (TGF)-β1. Methods and Results: AFs were cultured by the explant method. Western blot and immunocytochemistry were applied for α-smooth muscle actin (SMA) or protein kinase C (PKC) α protein analysis. Results showed that TGF-β1 upregulated PDE1A protein expression in rat aortic AFs and pharmacological inhibition of PDE1A blocked TGF-β1-induced α-SMA expression, a marker of myofibroblast formation, suggesting that the upregulation of PDE1A may mediate TGF-β1-induced AF transformation. Moreover, calphostin C (a PKC inhibitor) inhibited TGF-β1-induced α-SMA expression, whereas phorbol-12-myristate-13-acetate (a PKC activator) induced it. Finally, the upregulation of PKCα expression by TGF-β1 was also inhibited by PDE1A inhibition. Conclusions: Taken together, our data suggest that TGFβ1 induces α-SMA expression and myofibroblast formation via a PDE1A-PKCα-dependent mechanism. Our study thus unveils a novel signaling mechanism underlying TGF-β1-induced adventitial myofibroblast formation. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]