No abstract

Kcnq1 overlapping transcript 1 (kcnq1ot1), an imprinted antisense lncRNA in the kcnq1 locus, acts as a potential contributor to cardiovascular disease, but its role in atherosclerosis remains unknown. The aim of this study was to explore the effects of kcnq1ot1 on atherogenesis and the underlying mechanism. Our results showed that kcnq1ot1 expression was significantly increased in mouse aorta with atherosclerosis and lipid-loaded macrophages. Lentivirus-mediated kcnq1ot1 overexpression markedly increased atherosclerotic plaque area and decreased plasma HDL-C levels and RCT efficiency in apoE−/− mice fed a Western diet. Upregulation of kcnq1ot1 also reduced the expression of miR-452-3p and ABCA1 but increased HDAC3 levels in mouse aorta and THP-1 macrophages. Accordingly, kcnq1ot1 overexpression inhibited cholesterol efflux and promoted lipid accumulation in THP-1 macrophages. In contrast, kcnq1ot1 knockdown protected against atherosclerosis in apoE−/− mice and suppressed lipid accumulation in THP-1 macrophages. Mechanistically, kcnq1ot1 enhanced HDAC3 expression by competitively binding to miR-452-3p, thereby inhibiting ABCA1 expression and subsequent cholesterol efflux. Taken together, these findings suggest that kcnq1ot1 promotes macrophage lipid accumulation and accelerates the development of atherosclerosis through the miR-452-3p/HDAC3/ABCA1 pathway.

Biochanin A (BCA), a dietary isoflavone extracted from red clover and cabbage, has been shown to antagonize hypertension and myocardial ischemia/reperfusion injury. However, very little is known about its role in atherogenesis. The aim of this study was to observe the effects of BCA on atherosclerosis and explore the underlying mechanisms. Our results showed that administration of BCA promoted reverse cholesterol transport (RCT), improved plasma lipid profile, and decreased serum proinflammatory cytokine levels and atherosclerotic lesion area in apoE-/- mice fed a Western diet. In THP-1 macrophage-derived foam cells, treatment with BCA upregulated ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG1 expression and facilitated subsequent cholesterol efflux and diminished intracellular cholesterol contents by activating the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) and PPARγ/heme oxygenase 1 (HO-1) pathways. BCA also activated these two signaling pathways to inhibit the secretion of proinflammatory cytokines. Taken together, these findings suggest that BCA is protective against atherosclerosis by inhibiting lipid accumulation and inflammatory response through the PPARγ/LXRα and PPARγ/HO-1 pathways. BCA may be an attractive drug for the prevention and treatment of atherosclerotic cardiovascular disease.

C1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.

No abstract

Prevention of ATP binding cassette transporter A1 (ABCA1)‐dependent cholesterol efflux leads to lipid accumulation in macrophages and atherosclerosis development. C1q tumor necrosis factor‐related protein 1 (CTRP1), a conserved paralog of adiponectin, has been shown to aggravate atherosclerosis via its proinflammatory property. However, very little is known about its effects on ABCA1 expression and macrophage lipid accumulation. In the current studies, we found that CTRP1 downregulated ABCA1 expression, inhibited cholesterol efflux to apoA‐I and promoted lipid accumulation in THP‐1 macrophage‐derived foam cells. Forkhead box O1 (FoxO1), a transcriptional repressor of ABCA1, was identified as a direct target of miR‐424‐5p. Mechanistically, CTRP1 attenuated miR‐424‐5p levels and then augmented FoxO1 expression in the nucleus, which led to downregulation of ABCA1 expression and inhibition of cholesterol efflux. In conclusion, these findings suggest that CTRP1 restrains cholesterol efflux and facilitates macrophage lipid accumulation through the miR‐424‐5p/FoxO1/ABCA1 signaling pathway, thereby providing a novel mechanistical insight into its proatherosclerotic action.

No abstract

Background: α 2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α 2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α 2A-AR subtype of traditional drugs greatly limits their clinic usage. Methods: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α 2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. Results: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α 2A-AR over α 2B-and α 2C-ARs. Besides, the affinities are of similar linker lengthdependence for each α 2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α 2A-AR (pKi=−7.45±0.62), which is 12-fold and 60-fold selective over α 2B-AR and α 2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α 2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99. Conclusion: The specificity of C10 for the α 2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α 2A-AR subtype selective compounds.