RESUMO
Increased glycolysis is involved in the proliferation and migration of vascular smooth muscle cells (VSMCs). Pyruvate kinase isoform M2 (PKM2), a key rate-limiting enzyme in glycolysis, accelerates the proliferation and migration of tumor cells. Although the intracellular mechanisms associated with oxidized low-density lipoprotein (oxLDL)-stimulated VSMC proliferation and migration have been extensively explored, it is still unclear whether oxLDL promotes the proliferation and migration of VSMCs by enhancing PKM2-dependent glycolysis. In the present study, we detected PKM2 expression and pyruvate kinase activity in oxLDL-treated VSMCs and explored the regulation of PKM2 in oxLDL-treated VSMCs and apoE-/- mice. The results showed that PKM2 expression in VSMCs was higher in the intima than in the media in plaques from atherosclerotic rabbits. Moreover, PKM2 level in VSMCs was increased during atherosclerosis progression in apoE-/- mice. Both PKM2 expression and pyruvate kinase activity were found to be upregulated by oxLDL stimulation in VSMCs. Shikonin (SKN), a specific inhibitor of PKM2, was found to inhibit the oxLDL-induced proliferation and migration in VSMCs, in addition to delaying the atherosclerosis progression in apoE-/- mice. More importantly, oxLDL increased glucose uptake, ATP and lactate production, and the extracellular acidification rate in VSMCs, which could be reversed by SKN. Meanwhile, oxygen consumption rate was unchanged after oxLDL stimulation, suggesting that glycolysis is the main contributor to the energy supply in oxLDL-treated VSMCs. Our results suggest that oxLDL induces VSMC proliferation and migration by upregulating PKM2-dependent glycolysis, thereby contributing to the atherosclerosis progression. Thus, targeting PKM2-dependent glycolysis might provide a novel therapeutic approach for the treatment of atherosclerosis.
Assuntos
Aterosclerose/metabolismo , Proteínas de Transporte/metabolismo , Movimento Celular , Proliferação de Células , Glicólise/genética , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Piruvato Quinase/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout para ApoE , Naftoquinonas/farmacologia , Piruvato Quinase/antagonistas & inibidores , Piruvato Quinase/genética , Coelhos , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/genética , Proteínas de Ligação a Hormônio da TireoideRESUMO
Utilizing softly confined self-assembly at the water surface represents a promising approach for the fabrication of two-dimensional molecular monolayers (2D MMs), which have predominantly been concentrated on amphiphilic organic compounds before. Herein, we introduce a straightforward method termed "water surface-assisted molecular deposition (WSAMD)" to organize nonamphiphilic molecules into dense monolayers with high reproducibility. To underscore the versatility and merit of this methodology in the field of supramolecular electronics, we have successfully fabricated a range of defect-free, uniform semiconducting polymer monolayers, featuring a thickness reflective of molecular architectures. The charge carrier mobility could reach 0.05 cm2 V-1 s-1 for holes and 3.5 × 10-4 cm2 V-1 s-1 for electrons, respectively, in p-type and n-type polymeric monolayers when tested as the active layer in field-effect transistors. Furthermore, in situ polymerization reactions can be exploited to generate conductive monolayers of macromolecules such as polybenzylaniline (PBnANI) and polypyrrole (PPy), where PBnANI monolayers exhibit channel length-dependent conductivity, up to 0.37 S cm-1. The advent of the WSAMD method heralds a significant leap forward in the advancement of molecular 2D materials, catalyzing new avenues of exploration within material chemistry.
RESUMO
Disruption of re-endothelialization and haemodynamic balance remains a critical side effect of drug-eluting stents (DES) for preventing intimal hyperplasia. Previously, we found that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) suppressed macrophage-mediated inflammation in atherosclerotic plaques. However, the effects on intimal hyperplasia and re-endothelialization remain unknown. In this study, 56 rabbits were randomly assigned to control, ultrasound, ALA and ALA-SDT groups, and each group was divided into two subgroups (n = 7) on day 3 after right femoral artery balloon denudation combined with a hypercholesterolemic diet. Histopathological analysis revealed that ALA-SDT enhanced macrophage apoptosis and ameliorated inflammation from day 1. ALA-SDT inhibited neointima formation without affecting re-endothelialization, increased blood perfusion, decreased the content of macrophages, proliferating smooth muscle cells (SMCs) and collagen but increased elastin by day 28. In vitro, ALA-SDT induced macrophage apoptosis and reduced TNF-α, IL-6 and IL-1ß via the ROS-PPARγ-NF-κB signalling pathway, which indirectly inhibited human umbilical artery smooth muscle cell (HUASMC) proliferation, migration and IL-6 production. ALA-SDT effectively inhibits intimal hyperplasia without affecting re-endothelialization. Hence, its clinical application combined with bare-metal stent (BMS) implantation presents a potential strategy to decrease bleeding risk caused by prolonged dual-antiplatelet regimen after DES deployment.
Assuntos
Hiperplasia/tratamento farmacológico , Macrófagos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Neointima/tratamento farmacológico , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose , Linhagem Celular , Movimento Celular , Proliferação de Células , Colesterol/sangue , Técnicas de Cocultura , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Masculino , Placa Aterosclerótica/tratamento farmacológico , Coelhos , Distribuição Aleatória , Transdução de Sinais , Células THP-1 , Tomografia de Coerência ÓpticaRESUMO
During atherosclerosis plaque progression, pathological intraplaque angiogenesis leads to plaque rupture accompanied by thrombosis, which is probably the most important cause of arteries complications such as cerebral and myocardial infarction. Even though few treatments are available to mitigate plaque rupture, further investigation is required to develop a robust optimized therapeutic method. In this study using rabbit and mouse atherosclerotic models, sinoporphyrin sodium (DVDMS)-mediated sonodynamic therapy reduced abnormal angiogenesis and plaque rupture. Briefly, DVDMS is injected to animals, and then the plaque was locally exposed to pulse ultrasound for a few minutes. Furthermore, a small size clinical trial was conducted on patients with atherosclerosis. Notably, a significant reduction of arterial inflammation and angiogenesis was recorded following a short period of DVDMS-mediated sonodynamic therapy treatment. This beneficial outcome was almost equivalent to the therapeutic outcome after 3-month intensive statin treatment.