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1.
J Am Soc Nephrol ; 32(6): 1371-1388, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33758009

RESUMEN

BACKGROUND: Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. METHODS: Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. RESULTS: Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes. CONCLUSIONS: Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.


Asunto(s)
Envejecimiento , Proteoglicanos de Heparán Sulfato/metabolismo , Hipercolesterolemia/metabolismo , Hígado/metabolismo , Proproteína Convertasa 9/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Colesterol/sangre , Creatinina/sangre , Disacáridos/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Proteoglicanos de Heparán Sulfato/análogos & derivados , Hipercolesterolemia/complicaciones , Hipertensión/complicaciones , Hipertensión/metabolismo , Lipoproteínas VLDL/metabolismo , Masculino , N-Acetilglucosaminiltransferasas/genética , Nefrectomía , Proproteína Convertasa 9/genética , Ratas Wistar , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Sindecano-1/genética , Sindecano-1/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(16): 8890-8899, 2020 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-32245806

RESUMEN

Eastern equine encephalitis virus (EEEV), a mosquito-borne icosahedral alphavirus found mainly in North America, causes human and equine neurotropic infections. EEEV neurovirulence is influenced by the interaction of the viral envelope protein E2 with heparan sulfate (HS) proteoglycans from the host's plasma membrane during virus entry. Here, we present a 5.8-Å cryoelectron microscopy (cryo-EM) structure of EEEV complexed with the HS analog heparin. "Peripheral" HS binding sites were found to be associated with the base of each of the E2 glycoproteins that form the 60 quasi-threefold spikes (q3) and the 20 sites associated with the icosahedral threefold axes (i3). In addition, there is one HS site at the vertex of each q3 and i3 spike (the "axial" sites). Both the axial and peripheral sites are surrounded by basic residues, suggesting an electrostatic mechanism for HS binding. These residues are highly conserved among EEEV strains, and therefore a change in these residues might be linked to EEEV neurovirulence.


Asunto(s)
Diseño de Fármacos , Virus de la Encefalitis Equina del Este/ultraestructura , Encefalomielitis Equina/tratamiento farmacológico , Proteoglicanos de Heparán Sulfato/metabolismo , Heparina/ultraestructura , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Sitios de Unión/efectos de los fármacos , Línea Celular , Sulfatos de Condroitina/farmacología , Microscopía por Crioelectrón , Virus de la Encefalitis Equina del Este/metabolismo , Encefalomielitis Equina/virología , Proteoglicanos de Heparán Sulfato/análogos & derivados , Heparina/metabolismo , Humanos , Mesocricetus , Estructura Molecular , Relación Estructura-Actividad , Proteínas del Envoltorio Viral/metabolismo , Proteínas del Envoltorio Viral/ultraestructura , Acoplamiento Viral/efectos de los fármacos
3.
ACS Nano ; 12(7): 6429-6442, 2018 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-29894156

RESUMEN

The entry process of viruses into host cells is complex and involves stable but transient multivalent interactions with different cell surface receptors. The initial contact of several viruses begins with attachment to heparan sulfate (HS) proteoglycans on the cell surface, which results in a cascade of events that end up with virus entry. The development of antiviral agents based on multivalent interactions to shield virus particles and block initial interactions with cellular receptors has attracted attention in antiviral research. Here, we designed nanogels with different degrees of flexibility based on dendritic polyglycerol sulfate to mimic cellular HS. The designed nanogels are nontoxic and broad-spectrum, can multivalently interact with viral glycoproteins, shield virus surfaces, and efficiently block infection. We also visualized virus-nanogel interactions as well as the uptake of nanogels by the cells through clathrin-mediated endocytosis using confocal microscopy. As many human viruses attach to the cells through HS moieties, we introduce our flexible nanogels as robust inhibitors for these viruses.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Geles/química , Geles/farmacología , Glicerol/química , Glicerol/farmacología , Polímeros/química , Polímeros/farmacología , Internalización del Virus/efectos de los fármacos , Animales , Línea Celular , Chlorocebus aethiops , Química Clic , Proteoglicanos de Heparán Sulfato/análogos & derivados , Proteoglicanos de Heparán Sulfato/farmacología , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Modelos Moleculares , Nanopartículas/química , Células Vero
4.
Arterioscler Thromb Vasc Biol ; 25(1): 71-6, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15514208

RESUMEN

OBJECTIVE: Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives. METHODS AND RESULTS: Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and alpha(v)beta3 integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/alpha(v)beta3 integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane. CONCLUSIONS: LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/alpha(v)beta3 interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds.


Asunto(s)
Inhibidores de la Angiogénesis/biosíntesis , Escherichia coli/química , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Ingeniería Genética/métodos , Heparina de Bajo-Peso-Molecular/biosíntesis , Polisacáridos Bacterianos/biosíntesis , Inhibidores de la Angiogénesis/genética , Animales , Cápsulas Bacterianas , Células CHO/química , Células CHO/metabolismo , Bovinos , Adhesión Celular/fisiología , Línea Celular , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Membrana Corioalantoides/efectos de los fármacos , Cricetinae , Cricetulus , Células Endoteliales/química , Células Endoteliales/metabolismo , Escherichia coli/genética , Factor 2 de Crecimiento de Fibroblastos/análogos & derivados , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/análogos & derivados , Factores de Crecimiento de Fibroblastos/metabolismo , Proteoglicanos de Heparán Sulfato/análogos & derivados , Proteoglicanos de Heparán Sulfato/deficiencia , Proteoglicanos de Heparán Sulfato/metabolismo , Heparina de Bajo-Peso-Molecular/síntesis química , Heparina de Bajo-Peso-Molecular/genética , Integrina alfaVbeta3/metabolismo , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Polisacáridos Bacterianos/genética
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