Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes

Rebalka, Irena A.; Raleigh, Matthew J.; D’Souza, Donna M.; Coleman, Samantha K.; Rebalka, Alexandra N.; Hawke, Thomas J.

doi:10.2337/db14-1174

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…We further found that PAI-1 deficiency or PAI-039 treatment caused a significant reduction in a subset of M1 macrophage-specific genes in WAT of HFD-fed mice compared to HFD-WT mice. While this is apparent contrast to the studies of Rebalka et al (Rebalka et al, 2015 ), who reported that PAI-039 had little effect on M1 macrophages while increasing an M2a subset, their studies used a streptozotocin-induced model of diabetes, examined wound tissue as opposed to adipocytes and used a shorter duration of treatment with the inhibitor. The data from the present study suggest that genetic deletion and pharmacological inhibition of PAI-1 will cause a shift in WAT from an M1-mediated inflammatory environment to a relatively anti-inflammatory condition.…”

Section: Discussionmentioning

confidence: 66%

“…In terms of an interaction with inflammation, macrophage infiltration of WAT leads to increased lipolysis through the increased release of cytokines while TNF-α has been linked to PAI-1 expression in human adipose tissue explants and obese mice (Samad et al, 1999 ; Alessi and Juhan, 2006 ). Further supporting a relationship between PAI-1 and tissue macrophage infiltration, increased numbers of macrophages have been shown in lung exudates in the presence of PAI-1, while inhibition of PAI-1 by the administration of a small-molecule PAI-1 inhibitor attenuated infiltration of these cells (Ichimura et al, 2013 ; Osterholzer et al, 2013 ; Rebalka et al, 2015 ). Thus, collectively, these prior observations suggest a possible role for AT PAI-1 in the progression obesity and point to a need to clearly define such relationships.…”

Section: Introductionmentioning

confidence: 86%

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PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

et al. 2018

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Background: Plasminogen activator inhibitor (PAI)-1 levels and activity are known to increase during metabolic syndrome and obesity. In addition, previous studies have implicated PAI-1 in adipose tissue (AT) expansion while also contributing to insulin resistance. As inflammation is also known to occur in AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model PAI-1 contributes to macrophage-mediated inflammation and metabolic dysfunction.Methods: Four- to five-weeks-old male C57B6/6J mice were fed a HFD (45%) for 14 weeks, while age-matched control mice were fed a standard laboratory chow diet (10% fat). Additional studies were performed in PAI-1 knockout mice and wild type mice treated with an inhibitor (PAI-039) of PAI-1. Macrophage polarization were measured by real time PCR.Results: HFD mice showed increased expression of PAI-1 in visceral white AT (WAT) that also displayed increased macrophage numbers. PAI-1 deficient mice exhibited increased numbers of anti-inflammatory macrophages in WAT and were resistant to HFD-induced obesity. Similarly, pharmacological inhibition of PAI-1 using PAI-039 significantly decreased macrophage infiltration in WAT and improved metabolic status in HFD-induced wild-type mice. Importantly, the numbers of M1 macrophages appeared to be increased by the HFD and decreased by either genetic PAI-1 depletion or PAI-039 treatment.Conclusions: Collectively, our findings provide support for PAI-1 contributing to the development of inflammation in adipose tissue and explain the mechanism of inflammation modulated by PAI-1 in the disordered metabolism in HFD-induced obesity.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 86%

PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

et al. 2018

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“…To allow mice to develop chronic complications of diabetes like microangiopathies, a delay of 4, 5 and 7 weeks was allowed between the occurrence of the diabetic state (confirmed by glycaemia measurements) and the wound surgery. This is the range classically mentioned in wound healing studies using this model [ 71 , 72 ]. Nevertheless, even 7 weeks after the occurrence of the diabetic state, only a slight effect of diabetes was observed on wound healing kinetics.…”

Section: Discussionmentioning

confidence: 98%

Application of Electron Paramagnetic Resonance (EPR) Oximetry to Monitor Oxygen in Wounds in Diabetic Models

et al. 2015

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A lack of oxygen is classically described as a major cause of impaired wound healing in diabetic patients. Even if the role of oxygen in the wound healing process is well recognized, measurement of oxygen levels in a wound remains challenging. The purpose of the present study was to assess the value of electron paramagnetic resonance (EPR) oximetry to monitor pO2 in wounds during the healing process in diabetic mouse models. Kinetics of wound closure were carried out in streptozotocin (STZ)-treated and db/db mice. The pO2 was followed repeatedly during the healing process by 1 GHz EPR spectroscopy with lithium phthalocyanine (LiPc) crystals used as oxygen sensor in two different wound models: a full-thickness excisional skin wound and a pedicled skin flap. Wound closure kinetics were dramatically slower in 12-week-old db/db compared to control (db/+) mice, whereas kinetics were not statistically different in STZ-treated compared to control mice. At the center of excisional wounds, measurements were highly influenced by atmospheric oxygen early in the healing process. In pedicled flaps, hypoxia was observed early after wounding. While reoxygenation occurred over time in db/+ mice, hypoxia was prolonged in the diabetic db/db model. This observation was consistent with impaired healing and microangiopathies observed using intravital microscopy. In conclusion, EPR oximetry using LiPc crystals as the oxygen sensor is an appropriate technique to follow wound oxygenation in acute and chronic wounds, in normal and diabetic animals. Nevertheless, the technique is limited for measurements in pedicled skin flaps and cannot be applied to excisional wounds in which diffusion of atmospheric oxygen significantly affects the measurements.

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“…A recent study showed that PAI-039 induces apoptosis of SMCs, thereby producing an anti-proliferative effect, 49 , which is consistent with the known anti-apoptotic properties of PAI-1. 20, 22 In addition, another recent study demonstrated that PAI-039 improved dermal wound closure in diabetic mice, 50 which is intriguing because vascular remodeling has been considered as a form of wound repair. 51 …”

Section: Discussionmentioning

confidence: 99%

Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation

Weng

Fish

et al. 2016

ATVB

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Objective Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo. Approach and Results PAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its anti-migratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of STAT-1 in SMCs, but had no discernable effect on STAT-1 signaling in ECs. Expression of LDL receptor-related protein 1 (LRP1), a motogenic PAI-1 receptor that activates JAK/STAT-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury. Conclusions PAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which appears to be due to differences in PAI-1-dependent LRP1/JAK/STAT-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.

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Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes

Cited by 17 publications

References 37 publications

PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

Application of Electron Paramagnetic Resonance (EPR) Oximetry to Monitor Oxygen in Wounds in Diabetic Models

Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation

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