Doxorubicin (DOX), a widely used anti-tumor drug, can give rise to severe cardiotoxicity by oxidative stress and cell apoptosis, which restricts its clinical application. α-Linolenic acid (ALA) has been shown to serve as a potent cardioprotective agent. The aim of this study was to explore the protective effects of ALA on DOX-induced cardiotoxicity and the underlying molecular mechanisms for this cardioprotection in rats. Rats were randomly divided into four groups and administrated with normal saline, ALA (500 µg/kg), DOX (2.5 mg/kg), or ALA (500 µg/kg) plus DOX (2.5 mg/kg) for 17 days. The results showed that DOX treatment significantly increased the heart weight/body weight, liver wet weight (WW)/dry weight (DW), lung WW/DW, serum levels of brain natriuretic peptide, creatine kinase-MB, lactate dehydrogenase, and cardiac troponin I, myocardial necrosis and myocardial malondialdehyde content, and induced the mRNA expression of Nrf2 in the nucleus, cleaved caspase-3, Bax, and superoxide dismutase (SOD). In addition, DOX led to a significant decrease in left ventricular end-diastolic volume, stroke volume, ejection fraction, SOD, glutathione-peroxidase, catalase, as well as the expression of Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, phospho-AKT, phospho-ERK, and Bcl-2. Co-treatment with ALA significantly eliminated these changes induced by DOX except further reduction of Keap1 and elevation of Nrf2 and SOD mRNA. These results showed the cardioprotective effects of ALA on DOX-induced cardiotoxicity in rats. The mechanisms might be associated with the enhancement of antioxidant defense system through activating Keap1/Nrf2 pathway and anti-apoptosis through activating protein kinase B/extracellular signal regulated kinase pathway. Our results suggested a promising future of ALA-based preventions and therapies for myocardial damage after administration of DOX.
Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the arterial intima. The activated macrophages secreted more pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-␣, which promote the development of the disease. Apolipoprotein A-I (apoA-I), the major component of high density lipoprotein, is involved in reverse cholesterol transport of lipid metabolism. Recently, it has been found that apoA-I suppresses inflammation via repression of inflammatory cytokine expression; the mechanisms of the apoA-I-suppressive action, however, are not yet well characterized. In this study, we have for the first time found that apoA-I suppresses the expression of some inflammatory cytokines induced by lipopolysaccharide via a specific post-transcriptional regulation process, namely mRNA destabilization, in macrophages. Our further studies have also shown that AU-rich elements in the 3-untranslated region of TNF-␣ mRNA are responsive to the apoA-I-mediated mRNA destabilization. The apoA-I-induced inflammatory cytokine mRNA destabilization was associated with increased expression of mRNA-destabilizing protein tristetraprolin through a JAK2/STAT3 signaling pathway-dependent manner. When blocking interaction of apoA-I with ATPbinding membrane cassette transporter A1 (ABCA1), a major receptor for apoA-I in macrophages, it would almost totally abolish the effect of apoA-I on tristetraprolin expression. These results present not only a novel mechanism for the apoA-I-mediated inflammation suppression in macrophages but also provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis.
Aim: To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis. Methods: Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays. Results: Ibrolipim 5 and 50 μmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apoA-I or HDL. Moreover, it upregulated the expression of ABCA1 and ABCG1. In addition, LXRα was also upregulated by the ibrolipim treatment. In addition, LXRα small interfering RNA completely abolished the promotion effect that was induced by ibrolipim. Conclusion: Ibrolipim increased ABCA1 and ABCG1 expression and promoted cholesterol efflux, which was mediated by the LXRα signaling pathway.Keywords: ATP-binding membrane cassette transporter A-1; ATP-binding membrane cassette transporter G-1; ibrolipim; liver X receptor α; atherosclerosis; RNA interference; high density lipoprotein; apolipoprotein; cholesterol Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1343Sinica ( -1349 doi: 10.1038/aps.2010 published online 27 Sep 2010 Original Article # The first two authors contributed equally to this work. * To whom correspondence should be addressed.E-mail tchaoke@yahoo.com.cn Received 2010-04-26 Accepted 2010-08-17 (ABCG1) [4,5] .Ibrolipim is an effective lipoprotein lipase (LPL) activator [6] . It has previously been reported that ibrolipim increases lipoprotein lipase (LPL) mRNA in tissues and LPL activity in postheparin plasma, resulting in a reduction in plasma triglyceride levels and an elevation of HDL. Previous studies from our laboratory and others have also shown that increasing LPL activity in skeletal muscle results in decreased fat accumulation, and long-term administration of ibrolipim protects against the development of experimental atherosclerosis in animals [6][7][8] . However, the detailed mechanism for cholesterol transport proteins induced by ibrolipim is unclear.Recently, our laboratory revealed that the liver X receptors (LXR) synthetic agonist T0901317 promoted ABCA1 gene and protein levels in the aorta, liver, and small intestine of apoE-/-mice and significantly increased cholesterol efflux from peritoneal macrophages [9] . We also showed that IFN-γ may first downregulate the expression of LXRα through the 1344 www.nature.com/aps Chen SG et al Acta Pharmacologica Sinica npg JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophagederived foam cells [10] . In addition, eicosapentaenoic acid (EPA) reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through a cAMP/PKA pathway in THP-1 macrophage-derived foam cells [1...
Adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a crucial role in apolipoprotein A-I (apoA-I) binding activity and promotes cellular cholesterol efflux. ApoA-I mimetic peptide D4-F has reported to have the similar ability as apoA-I. However, the detailed mechanisms of ABCA1 regulation by D4-F are not understood. In the present study, we investigated the effects of D4-F on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of Cdc42/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway on the regulation of ABCA1 by D4-F in THP-1 macrophage-derived foam cells. Results showed that D4-F stabilized ABCA1 protein and enhanced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 messenger RNA expression. We also revealed that D4-F enhanced cAMP level and PKA activity and ABCA1 serine phosphorylation. Short interfering RNA of PKA led to reduction of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux compensated by D4-F. PKA-specific activation by PKA agonist enhanced the upregulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by D4-F. However, ABCA1 expression did not change by treatment with PKA agonist or PKA-short interfering RNA. We found that secramine B of Cdc42 inhibitor reduced the cAMP level compensated by D4-F. These results provide evidence that D4-F enhances ABCA1 serine phosphorylation and ABCA1-dependent cholesterol efflux through Cdc42/cAMP/PKA pathway in THP-1 macrophage-derived foam cells.
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