RESUMO
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.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Aterosclerose/genética , Histona Desacetilases/metabolismo , Metabolismo dos Lipídeos/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/sangue , Sequência de Bases , Transporte Biológico , HDL-Colesterol/sangue , Regulação para Baixo/genética , Humanos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , RNA Longo não Codificante/genética , Células THP-1RESUMO
The development of atherosclerosis is accompanied by the functional deterioration of plaque cells, which leads to the escalation of endothelial inflammation, abnormal vascular smooth muscle cell phenotype switching and the accumulation of lipid-laden macrophages within vascular walls. Autophagy, a highly conserved homeostatic mechanism, is critical for the delivery of cytoplasmic substrates to lysosomes for degradation. Moderate levels of autophagy prevent atherosclerosis by safeguarding plaque cells against apoptosis, preventing inflammation, and limiting the lipid burden, whereas excessive autophagy exacerbates cell damage and inflammation and thereby accelerates the formation of atherosclerotic plaques. Increasing lines of evidence suggest that long noncoding RNAs can be either beneficial or detrimental to atherosclerosis development by regulating the autophagy level. This review summarizes the research progress related to 1) the significant role of autophagy in atherosclerosis and 2) the effects of the lncRNA-mediated modulation of autophagy on the plaque cell fate, inflammation levels, proliferative capacity, and cholesterol metabolism and subsequently on atherogenesis.
Assuntos
Artérias/metabolismo , Aterosclerose/metabolismo , Autofagia , Placa Aterosclerótica , RNA Longo não Codificante/metabolismo , Animais , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/terapia , Proteínas Relacionadas à Autofagia/metabolismo , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , RNA Longo não Codificante/genética , Transdução de SinaisRESUMO
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.
