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ABSTRACT: Whether the current pharmacogenetic knowledge of clopidogrel could be translated into Chinese clinical practice is yet to be defined. To address this issue, we assessed the relation of single nucleotide polymorphisms within genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP2B6, CYP2D6, CYP3A4, CYP2C9, and CYP2C19), and biologic activity (P2RY12) to the response of clopidogrel as measured by ex-vivo platelet reactivity and ischemic events during half a year of follow-up. Only CYP2C19*2 and *3, of the investigated polymorphisms, were associated with postclopidogrel platelet aggregation and the presence of high platelet reactivity. Moreover, the effect of the CYP2C19*2 versus the *3 allele on platelet reactivity did not differ. Although the carriage of one or two CYP2C19 loss-of-function alleles, irrespective of the CYP2C19*2 or *3 allele, increased the propensity for high platelet reactivity, only the two loss-of-function allele carriage was associated with clinical outcome in the first 6 months.
Pharmacogenetics and Genomics 09/2012; · 3.48 Impact Factor
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International journal of cardiology 09/2012; · 7.08 Impact Factor
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ABSTRACT: High-density lipoprotein (HDL) possesses protective properties in cardiovascular diseases. However, the effect of HDL on the mesenchymal stem cells (MSCs), which could be mobilized to the damaged myocardial tissue, has not been well elucidated yet. In the current study, we investigated the effect of HDL on the proliferation of MSCs so as to reveal its molecular mechanisms. MSCs derived from rats were treated with HDL in different concentrations and for different periods. The proliferation of MSCs was measured with MTT and BrdU cell proliferation assay. The phosphorylation of Akt, ERK1/2 and the expression of p21 were evaluated by Western blotting. After the activity of respective pathways was down-regulated by the specific inhibitor and the gene of scavenger receptor-B type I (SR-BI) was knocked down by RNA interference, BrdU assay was performed to examine this effect of HDL on MSCs. We found that the proliferation of MSCs induced by HDL, in a time- and concentration-dependent manner, was the phosphorylation of Akt- and ERK1/2-dependent, which was significantly attenuated by the specific inhibitor to respective pathways. Moreover, MAPK/ERK1/2 pathway exerted a more dominating effect on this process. SR-BI contributed to HDL-induced proliferation of MSCs, which was effectively abolished by the silencing of SR-BI. The results suggested that HDL was capable of improving MSCs proliferation, in which MAPK/ERK1/2 and PI3K/Akt pathways involved and SR-BI played a critical role as well.
Molecular and Cellular Biochemistry 08/2012; · 2.06 Impact Factor
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ABSTRACT: The therapeutic effect of transplantation of mesenchymal stem cells (MSCs) in myocardial infarction (MI) appears to be limited by poor cell viability in the injured tissue, which is a consequence of oxidative stress and pro-apoptotic factors. High density lipoprotein (HDL) reverses cholesterol transport and has anti-oxidative and anti-apoptotic properties. We, therefore, investigated whether HDL could protect MSCs from oxidative stress-induced apoptosis. MSCs derived from the bone marrow of rats were pre-incubated with or without HDL, and then were exposed to hydrogen peroxide (H(2)O(2)) in vitro, or were transplanted into experimentally infarcted hearts of rats in vivo. Pre-incubation of MSCs with HDL increased cell viability, reduced apoptotic indices and resulted in parallel decreases in reactive oxygen species (ROS) in comparison with control MSCs. Each of the beneficial effects of HDL on MSCs was attenuated by inhibiting the PI3K/Akt pathway. Preconditioning with HDL resulted in higher MSC survival rates, improved cardiac remodeling and better myocardial function than in the MSC control group. Collectively, these results suggest that HDL may protect against H(2)O(2)-induced apoptosis in MSCs through activation of a PI3K/Akt pathway, and by suppressing the production of ROS.
International Journal of Molecular Sciences 01/2012; 13(12):17104-20. · 2.60 Impact Factor
