RESUMO
Atherosclerotic cardiovascular disease is considered as the leading cause of mortality and morbidity worldwide. Accumulating evidence supports an important role for long noncoding RNA (lncRNA) in the pathogenesis of atherosclerosis. Nevertheless, the role of lncRNA in atherosclerosis-associated vascular dysfunction and the underlying mechanism remain elusive. Here, using microarray analysis, we identified a novel lncRNA RP11-714G18.1 with significant reduced expression in human advanced atherosclerotic plaque tissues. We demonstrated in both human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that RP11-714G18.1 impaired cell migration, reduced the adhesion of ECs to monocytes, suppressed the neoangiogenesis, decreased apoptosis of VSMCs and promoted nitric oxide production. Mechanistically, RP11-714G18.1 could directly bind to its nearby gene LRP2BP and increased the expression of LRP2BP. Moreover, we showed that RP11-714G18.1 impaired cell migration through LRP2BP-mediated downregulation of matrix metalloproteinase (MMP)1 in both ECs and VSMCs. In atherosclerotic patients, the serum levels of LRP2BP were positively correlated with high-density lipoprotein cholesterol, but negatively correlated with cardiac troponin I. Our study suggests that RP11-714G18.1 may play an athero-protective role by inhibiting vascular cell migration via RP11-714G18.1/LRP2BP/MMP1 signaling pathway, and targeting the pathway may provide new therapeutic approaches for atherosclerosis.
Assuntos
Proteínas de Transporte/metabolismo , Movimento Celular , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Sequência de Bases , Proteínas de Transporte/sangue , Proteínas de Transporte/genética , Adesão Celular/genética , Ciclo Celular/genética , Movimento Celular/genética , HDL-Colesterol/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Neovascularização Fisiológica , Óxido Nítrico/biossíntese , Fases de Leitura Aberta/genética , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , RNA Longo não Codificante/genética , Troponina I/metabolismoRESUMO
OBJECTIVE: Drug-eluting stent delivery of mTORC1 (mechanistic target of rapamycin complex 1) inhibitors is highly effective in preventing intimal hyperplasia after coronary revascularization, but adverse effects limit their use for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell differentiation in an AKT2-dependent manner in vitro. Here, we investigate the roles of AKT (protein kinase B) isoforms in intimal hyperplasia. APPROACH AND RESULTS: We found that germ-line-specific or smooth muscle-specific deletion of Akt2 resulted in more severe intimal hyperplasia compared with control mice after arterial denudation injury. Conversely, smooth muscle-specific Akt1 knockout prevented intimal hyperplasia, whereas germ-line Akt1 deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild-type mice but had no therapeutic benefit in Akt2 knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in smooth muscle cell proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced MYOCD (myocardin) mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4 (forkhead box O4), inhibiting its binding to the MYOCD promoter. CONCLUSIONS: Our data reveal opposing roles for AKT isoforms in smooth muscle cell remodeling. AKT2 is required for rapamycin's therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of MYOCD via FOXO4. Because AKT2 signaling is impaired in diabetes mellitus, this work has important implications for rapamycin therapy, particularly in diabetic patients.