Peptide Inhibitor of NF-κB Translocation Ameliorates Experimental Atherosclerosis

Mallavia, Beñat; Recio, Carlota; Oguiza, Ainhoa; Ortiz-Muñoz, Guadalupe; Lázaro, Iolanda; López-Parra, Virginia; López-Franco, Óscar; Schindler, Susanne; Depping, Reinhard; Egido, Jesús; Gómez-Guerrero, Carmen

doi:10.1016/j.ajpath.2013.01.022

Cited by 59 publications

(52 citation statements)

References 44 publications

(59 reference statements)

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“…Ranganathan and colleagues [105] used the selective nuclear export inhibitor KPT-sine (Karyopharm Therapeutics) in preclinical studies of acute myeloid leukemia. In line with this, Mallavia and colleagues [106] applied a specific peptide to inhibit nuclear import of NFκB in a model of experimental atherosclerosis. It might be well worth considering that the modulation of nuclear translocation of HIFs could provide therapeutic applicability to tumors.…”

Section: Discussionmentioning

confidence: 87%

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

2015

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In order to pass through the nuclear pore complex, proteins larger than ∼40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ∼100-120 kDa proteins, consisting of one out of three different O2-labile α subunits (primarily HIF-1α) and a more constitutive 1β subunit. In the presence of O2, the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1α and HIF-1β is mainly mediated by importins α and β (α/β). HIF-1α can shuttle between nucleus and cytoplasm, while HIF-1β is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin α/β receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1α occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin α/β receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases.

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Section: Discussionmentioning

confidence: 87%

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

2015

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“…Dysregulated NF-kB and STAT pathways contribute to diabetic nephropathy and atherosclerosis by inducing the transcription of many genes associated with inflammation, renal fibrosis (45)(46)(47), and the proatherogenic state (23,48). We have previously tested a number of potential novel approaches (e.g., kinase inhibitors, permeable peptides, and gene therapy) to tackle diabetic nephropathy and atherosclerosis by separately inhibiting the STAT and NF-kB pathways (23,26,28,29). Here, we demonstrated that DMAG treatment resulted in combined inhibition of the NF-kB and STAT pathways and subsequent downregulation of their inducible genes (e.g., cytokines, chemokines, and extracellular matrix proteins) both in diabetic mice and in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Positive staining was expressed as percentage of total plaque area or number of positive cells per lesion area (26,27). Activated NF-kB in kidney and aorta was detected by Southwestern histochemistry using digoxigenin-labeled probes (26,28 (23). Murine monocyte/macrophage cell line (RAW 264.7, TIB-71; ATCC) was maintained in DMEM with 10% FBS.…”

Section: Histological Analysismentioning

confidence: 99%

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Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.

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“…Parallel sections were analyzed for collagen content (picrosirius red staining) and immunoperoxidase detection of T lymphocytes (CD4, BD Biosciences), macrophages (Moma2, Serotec, Oxford, UK), and monocyte chemoattractant protein-1 (CCL2, Santa Cruz Biotechnology, Santa Cruz, CA) as described [22]. STAT phosphorylation (P-STAT1, Santa Cruz Biotechnology; P-STAT3, Cell Signaling, Danvers, MA) and macrophage phenotypes (M1, arginase (Arg) II; M2, ArgI; Santa Cruz Biotechnology) were analyzed by immunofluorescence using Alexa Fluor 568 and 488 secondary antibodies (Invitrogen, Carlsbad, CA) followed by nuclear counterstain (4 0 ,6-diamidino-2-phenylindole) [18,22]. Appropriate antibodies were used as isotype controls.…”

Section: Atherosclerotic Lesion Analysismentioning

confidence: 99%

Gene delivery of suppressors of cytokine signaling (SOCS) inhibits inflammation and atherosclerosis development in mice

et al. 2015

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Chronic activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway contributes to vascular inflammation and atherosclerosis by inducing expression of genes involved in cell proliferation, differentiation and migration. We aimed to investigate whether enforced expression of negative regulators, the suppressors of cytokine signaling (SOCS1 and SOCS3), inhibits harmful JAK/STAT-mediated responses and affects atherosclerosis in apolipoprotein E knockout mice. Adenovirus-mediated SOCS1 transgene expression impaired the onset and progression of atherosclerosis without impact on lipid profile, whereas SOCS3 was only effective on early atherosclerosis. Mechanistically, SOCS gene delivery, primarily SOCS1, attenuated STAT1 and STAT3 activation and reduced the expression of STAT-dependent genes (chemokine/chemokine receptors, adhesion molecules, pro-inflammatory cytokines and scavenger receptors) in aortic tissue. Furthermore, atherosclerotic plaques exhibit a more stable phenotype characterized by lower lipids, T cells and M1 macrophages and higher M2 macrophages and collagen. Atheroprotection was accompanied by a systemic alteration of T helper- and T regulatory-related genes and a reduced activation state of circulating monocytes. In vascular smooth muscle cells and macrophages, SOCS gene delivery inhibited cytokine-induced STAT activation, pro-inflammatory gene expression, cell migration and proliferation. In conclusion, targeting SOCS proteins, predominantly SOCS1, to suppress pathological mechanisms involved in atheroma plaque progression and destabilization could be an interesting anti-atherosclerotic strategy.

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Peptide Inhibitor of NF-κB Translocation Ameliorates Experimental Atherosclerosis

Cited by 59 publications

References 44 publications

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Gene delivery of suppressors of cytokine signaling (SOCS) inhibits inflammation and atherosclerosis development in mice

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