RESUMO
[Figure: see text].
Assuntos
Aterosclerose/enzimologia , Colesterol/metabolismo , Células Espumosas/enzimologia , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Esterol Esterase/metabolismo , Animais , Aorta/enzimologia , Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Células Espumosas/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Células RAW 264.7RESUMO
In humans, smooth muscle cells (SMCs) are the main cell type in the artery medial layer, in pre-atherosclerotic diffuse thickening of the intima, and in all stages of atherosclerotic lesion development. SMCs secrete the proteoglycans responsible for the initial binding and retention of atherogenic lipoproteins in the artery intima, with this retention driving foam cell formation and subsequent stages of atherosclerosis. In this chapter we review current knowledge of the extracellular matrix generated by SMCs in medial and intimal arterial layers, their relationship to atherosclerotic lesion development and stabilization, how these findings correlate with mouse models of atherosclerosis, and potential therapies aimed at targeting the SMC matrix-lipoprotein interaction for atherosclerosis prevention.
Assuntos
Aterosclerose , Proteoglicanas , Animais , Aterosclerose/etiologia , Lipoproteínas , Camundongos , Músculo Liso Vascular , Miócitos de Músculo LisoRESUMO
PURPOSE OF REVIEW: Smooth muscle cells (SMCs) are the major cell type in human atherosclerosis-prone arteries and take up excess lipids, thereby contributing to luminal occlusion. Here we provide a focused review on pathways by which smooth muscle cells (SMCs) can become foam cells in atherosclerosis. RECENT FINDINGS: A synthesis of recent and older investigations provides key mechanistic insights into SMC foam cell formation. LDL and other apoB-containing lipoproteins are modified by a diverse array of oxidative, enzymatic, and nonenzymatic processes present in the arterial intima. These modifications of LDL all promote the aggregation of LDL (agLDL), a key finding from analysis of arterial lesion particles. Scavenger receptor and phagocytic capacity of SMCs can vary greatly, perhaps related to differences in SMC phenotype or in-vitro cell culture environments, and can be increased with exposure to cytokines, growth factors, and cholesterol. Macrophages promote the formation of SMC foam cells in direct or indirect co-culture models. SUMMARY: SMCs contribute significantly to the foam cell population in atherosclerosis. Further investigation and identification of key mechanisms of SMC foam cell formation will help drive new therapeutics to reduce cardiovascular disease.
Assuntos
Aterosclerose/metabolismo , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Miócitos de Músculo Liso/metabolismo , Túnica Íntima/metabolismo , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Diferenciação Celular , Técnicas de Cocultura , Citocinas/farmacologia , Células Espumosas/efeitos dos fármacos , Células Espumosas/patologia , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Lipoproteínas LDL/genética , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fagocitose , Agregados Proteicos/efeitos dos fármacos , Receptores Depuradores/genética , Receptores Depuradores/metabolismo , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologiaRESUMO
Extra domain B of fibronectin (FN-EDB) is upregulated in the extracellular matrix during tissue remodeling and has been postulated as a potential biomarker for atherosclerosis, yet no systematic test for FN-EDB in plaques has been reported. We hypothesized that FN-EDB expression would intensify in advanced plaques. Furthermore, engineering of FN-EDB-targeted nanoparticles (NPs) could enable imaging/diagnosis and local delivery of payloads to plaques. Methods: The amount of FN-EDB in human atherosclerotic and normal arteries (ages: 40 to 85 years) was assessed by histological staining and quantification using an FN-EDB-specific aptide (APTFN-EDB). FN-EDB-specific NPs that could serve as MRI beacons were constructed by immobilizing APTFN-EDB on the NP surface containing DTPA[Gd]. MRI visualized APTFN-EDB-[Gd]NPs administered to atherosclerotic apolipoprotein E-deficient mice in the brachiocephalic arteries. Analysis of the ascending-to-descending thoracic aortas and the aortic roots of the mice permitted quantitation of Gd, FN-EDB, and APTFN-EDB-[Gd]NPs. Cyanine, a model small molecule drug, was used to study the biodistribution and pharmacokinetics of APTFN-EDB-NPs to evaluate their utility for drug delivery. Results: Atherosclerotic tissues had significantly greater FN-EDB-positive areas than normal arteries (P < 0.001). This signal pertained particularly to Type III (P < 0.01), IV (P < 0.01), and V lesions (P < 0.001) rather than Type I and II lesions (AHA classification). FN-EDB expression was positively correlated with macrophage accumulation and neoangiogenesis. Quantitative analysis of T1-weighted images of atherosclerotic mice revealed substantial APTFN-EDB-[Gd]NPs accumulation in plaques compared to control NPs, conventional MRI contrast agent (Gd-DTPA) or accumulation in wild-type C57BL/6J mice. Additionally, the APTFN-EDB-NPs significantly prolonged the blood-circulation time (t1/2: ~ 6 h) of a model drug and increased its accumulation in plaques (6.9-fold higher accumulation vs. free drug). Conclusions: Our findings demonstrate augmented FN-EDB expression in Type III, IV, and V atheromata and that APTFN-EDB-NPs could serve as a platform for identifying and/or delivering agents locally to a subset of atherosclerotic plaques.
Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Fibronectinas/metabolismo , Imagem Molecular/métodos , Terapia de Alvo Molecular/métodos , Nanopartículas/metabolismo , Placa Aterosclerótica/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aptâmeros de Peptídeos/administração & dosagem , Aptâmeros de Peptídeos/metabolismo , Modelos Animais de Doenças , Feminino , Fibronectinas/análise , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Ligação ProteicaRESUMO
The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.