Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease

Johnson, Lynne L.; Johnson, Jordan; Ober, Rebecca A.; Holland, April; Zhang, Geping; Backer, Marina V.; Backer, Joseph M.; Ali, Ziad A.; Tekabe, Yared

doi:10.1161/jaha.120.016696

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…We treated diabetic mice with the murine anti‐RAGE Ab, and found that in mice treated with antibody, angiogenesis was enhanced compared with mice treated with vehicle. We extended this research to porcine model of diabetes with endovascular occlusion of the anterior femoral artery to show similar results of systemic administration of anti‐RAGE Ab to improve angiogenesis to the ischemic muscle in the limb occluded 30 . Other investigators demonstrated that soluble RAGE given as a decoy to diabetic db/db mice with full thickness dorsal wounds, showed accelerated wound healing in treated compared with untreated mice 6…”

Section: Discussionmentioning

confidence: 76%

“…We extended this research to porcine model of diabetes with endovascular occlusion of the anterior femoral artery to show similar results of systemic administration of anti-RAGE Ab to improve angiogenesis to the ischemic muscle in the limb occluded. 30 Other investigators demonstrated that soluble RAGE given as a decoy to diabetic db/db mice with full thickness dorsal wounds, showed accelerated wound healing in treated compared with untreated mice. 6 Local approaches to treat diabetic wounds have included sustained topical administration of drugs in patches.…”

Section: Discussionmentioning

confidence: 99%

“…As a result of its passive physical support for cells and its role in transducing signals pivotal for tissue repair, the ECM provides the scaffolding needed during each stage of the healing process. 29 , 30 , 32 , 33 The ECM patch acts as a physical placeholder for the missing tissue and if not immediately incorporated into the wound would act more like a dressing. In this study, we observed that the patches on the IgG treated pig tended to stay attached to the wound and showed partial incorporation into the wounds.…”

Section: Discussionmentioning

confidence: 99%

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Blocking RAGE improves wound healing in diabetic pigs

Johnson

Takebe

Zhang

et al. 2022

International Wound Journal

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Receptor for Advanced Glycated End‐products (RAGE) is highly expressed in diabetes and impairs wound healing. We proposed that administering an antibody that blocks RAGE will hasten the healing of dorsal wounds in diabetic pigs compared with a non‐immune IgG. Two purpose‐bred diabetic (D) Yucatan minipigs (Sinclair, Auxvasse MO) each underwent 12 2 × 2 cm full thickness dorsal wounds: four wounds received decellularized porcine skin patches (Xylyx Bio, Bklyn NY): four anti‐RAGE Ab (CR‐3) infused patches, four saline infused patches and four wounds were left open. One pig received anti‐RAGE Ab (CR‐3) 1 mg/kg IM q 10 days and other received non‐immune IgG. Wounds were measured at 2 and 4 weeks followed by euthanasia and wound harvesting. At 2 weeks few of the patches appeared to be incorporated into the wound. By 4 weeks all patches in pigs treated systemically with CR‐3 were detached and the wounds almost healed. For all 24 wounds for both pigs regardless of presence of patch or type of patch, the average IgG treated pig wound size at 4 weeks was 69.2 ± 14.6% of initial size and the average CR‐3 treated pig wound size was 40.9 ± 11.3% of initial size (P = 0.0002). Quantitative immunohistology showed greater staining for collagen in the CR‐3 treated wounds compared with IgG treated. Staining was positive for RAGE, Mac, and IL‐6 in the IgG treated wounds and negative in the CR‐3 treated wounds. From these pilot experiments, we conclude that a RAGE blocking antibody given parenterally improved wound healing in a diabetic pig while patches were not effective.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Blocking RAGE improves wound healing in diabetic pigs

Johnson

Takebe

Zhang

et al. 2022

International Wound Journal

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“…However, the precise consequences of treatment with AGE-disrupting drugs remain a matter of debate, and there is a need for additional strategies to minimize matrix protein glycosylation. Encouragingly, an anti-RAGE monoclonal antibody that binds a peptide sequence in the RAGE extracellular structural domain prevented receptor-ligand binding and significantly improved hindlimb perfusion in ischaemic limbs, with greater reconstruction of collateral circulation in occluded arteries [ 132 ]. Recombinant proteins containing ELP fused to the RAGE domain or to stromal cell-derived factor 1 can inhibit AGE-RAGE signal transduction and promote cell proliferation and angiogenesis [ 133 ].…”

Section: Therapeutic Strategies For Promoting Angiogenesis By Targeti...mentioning

confidence: 99%

Impaired angiogenesis in ageing: the central role of the extracellular matrix

et al. 2023

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Each step in angiogenesis is regulated by the extracellular matrix (ECM). Accumulating evidence indicates that ageing-related changes in the ECM driven by cellular senescence lead to a reduction in neovascularisation, reduced microvascular density, and an increased risk of tissue ischaemic injury. These changes can lead to health events that have major negative impacts on quality of life and place a significant financial burden on the healthcare system. Elucidating interactions between the ECM and cells during angiogenesis in the context of ageing is neceary to clarify the mechanisms underlying reduced angiogenesis in older adults. In this review, we summarize ageing-related changes in the composition, structure, and function of the ECM and their relevance for angiogenesis. Then, we explore in detail the mechanisms of interaction between the aged ECM and cells during impaired angiogenesis in the older population for the first time, discussing diseases caused by restricted angiogenesis. We also outline several novel pro-angiogenic therapeutic strategies targeting the ECM that can provide new insights into the choice of appropriate treatments for a variety of age-related diseases. Based on the knowledge gathered from recent reports and journal articles, we provide a better understanding of the mechanisms underlying impaired angiogenesis with age and contribute to the development of effective treatments that will enhance quality of life.

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“…It inhibited HMGB1-induced IL-6 secretion from human peripheral bone marrow cells. The peptide sequences of this antibody are the same as for the antibody referred to as CR-3 in our recent publications [11,12].…”

Section: Antibodiesmentioning

confidence: 99%

Blocking RAGE expression after injury reduces inflammation in mouse model of acute lung injury

et al. 2023

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Background Receptor for Advanced Glycated Endproducts (RAGE) plays a major role in the inflammatory response to infectious and toxin induced acute lung injury. We tested the hypothesis that a RAGE blocking antibody when administered after the onset of injury can reduce lung inflammation compared to control antibody. Methods Male and female C57BL/6 (WT) mice were used. Forty-six received lipopolysaccharide (LPS) and 26 PBS by nasal instillation on day one, repeated on day three. On day 2, 36 mice receiving LPS were divided into two groups of 18, one treated with 200 μg of non-immune isotype control IgG and the second group treated with 200 μg of anti-RAGE Ab, each dose divided between IV and IP. Ten of the 46 were not treated. On day 4, before euthanasia, mice were injected with fluorescein isothiocyanate (FITC) labelled albumen. BALF and serum samples were collected as well as lung tissue for immunohistochemistry (IHC). BALF was analyzed for cell (leukocyte) counts, for FITC BALF/serum ratios indicating pulmonary vascular leak, and for cytokines/chemokines using bead based multiplex assays. Quantitative IHC was performed for MPO and RAGE. Results Ten LPS mice showed minimal inflammation by all measures indicating poor delivery of LPS and were excluded from analysis leaving n = 11 in the LPS + IgG group and n = 12 in the LPS + anti-RAGE group. BALF cell counts were low in the PBS administered mice (4.9 ± 2.1 × 105/ml) and high in the LPS injured untreated mice (109 ± 34) and in the LPS + IgG mice (91 ± 54) while in comparison, LPS + anti-RAGE ab mice counts were significantly lower (51.3 ± 18 vs. LPS + IgG, P = 0.03). The BALF/serum FITC ratios were lower for the LPS + anti-RAGE mice than for the LPS + IgG mice indicating less capillary leakiness. Quantitative IHC RAGE staining was lower in the LPS + anti-RAGE ab mice than in the LPS + IgG treated mice (P = 0.02). Conclusions These results describe a four-day LPS protocol to sustain lung injury and allow for treatment and suggests that treatment aimed at blocking RAGE when given after onset of injury can reduce lung inflammation.

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Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease

Cited by 9 publications

References 35 publications

Blocking RAGE improves wound healing in diabetic pigs

Blocking RAGE improves wound healing in diabetic pigs

Impaired angiogenesis in ageing: the central role of the extracellular matrix

Blocking RAGE expression after injury reduces inflammation in mouse model of acute lung injury

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