Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis

Zhou, Xin; Patel, Darshan; Sen, Sabyasachi; Shanmugam, Victoria K.; Sidawy, Anton N.; Mishra, Lopa; Nguyen, Bao-Ngoc

doi:10.1016/j.jvs.2016.03.407

Cited by 27 publications

(14 citation statements)

References 34 publications

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“…The release of cytochrome c via this mechanism may be associated with the Bcl-2 family of proteins ( 40 , 42 ). When cytochrome c forms a complex with apoptotic protease-activating factor 1 apoptosomes are formed, which activate caspase-9 and consequently activate caspase-3 ( 43 ), DNA-breaking enzymes, including endonucleases ( 44 ), and repair enzymes, including poly ADP-ribose polymerase ( 45 ), leading to cell death. The extrinsic apoptosis pathway activates caspase-8, which either activates executioner caspases, such as caspase-3, or the intrinsic apoptotic pathway ( 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

Rhein protects against cerebral ischemic‑/reperfusion‑induced oxidative stress and apoptosis in rats

et al. 2018

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The present study aimed to investigate the protective effects of rhein on cerebral ischemic/reperfusion (I/R) injury in rats. The present study focused on the effect of rhein on oxidative stress and apoptotic factors, which are considered to serve an important role in the onset of I/R injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neurological functional scores (NFSs) were evaluated according to the Zea Longa's score criteria and the area of brain infarct was determined by triphenyltetrazolium chloride staining. The morphology of the nerve cells in the cortex was observed following hematoxylin and eosin staining. In addition, levels of oxidative stress were assessed by measuring the levels of superoxide dismutase (SOD), glutathione-peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA). Levels of B-cell lymphoma-2 (Bcl-2), apoptosis regulator Bax (BAX), caspase-9, caspase-3 and cleaved caspase-3 expression were analyzed using western blot analysis. Levels of caspase-9 and caspase-3 mRNA expression were obtained using reverse transcription-quantitative polymerase chain reaction. The results revealed that treatment with 50 or 100 mg/kg rhein significantly improved the NFS and markedly attenuated the area of infarction. Rhein also significantly reduced the content of MDA and significantly increased SOD, GSH-Px and CAT activity. Western blot analysis indicated that rhein significantly decreased the expression of BAX and enhanced the expression of Bcl-2. Compared with the I/R group, levels of caspase-9, caspase-3 and cleaved caspase-3 protein expression were significantly decreased in the rhein treatment groups. Additionally, rhein treatment significantly reduced levels of caspase-9 and caspase-3 mRNA expression. These results suggest that rhein exhibits protective effects during cerebral I/R injury and its underlying mechanism of action may involve the inhibition of oxidative stress and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Rhein protects against cerebral ischemic‑/reperfusion‑induced oxidative stress and apoptosis in rats

et al. 2018

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“…Although there are conflicting data on the role of PARP in angiogenesis (Rajesh et al, 2006;Pyriochou et al, 2008;Caldini et al, 2011;Binu et al, 2012;Guzyk et al, 2016), multiple lines of in vivo studies indicate that PARP inhibitors of various classes enhance wound healing (El-Hamoly et al, 2014;Sarras et al, 2014;Byun et al, 2015;El-Hamoly et al, 2015;Zhou et al, 2016). The current study adds burn injury to the list of conditions, where PARP inhibition may accelerate wound healing.…”

Section: Bjpmentioning

confidence: 85%

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third‐degree burn injury

Ahmad

Oláh

Herndon

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEThe PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients. EXPERIMENTAL APPROACHMice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg·kg À1 ·day À1 i.p.) groups. Outcome variables included indices of organ injury, clinical chemistry parameters, plasma levels of inflammatory mediators (at 24 h, 7 and 21 days) and burn wound size (at 21 days). KEY RESULTSOlaparib reduced myeloperoxidase levels in heart and lung homogenates and reduced malondialdehyde levels in all tissues 24 h post-burn. Olaparib also reduced circulating alkaline aminotransferase, amylase and blood urea nitrogen and creatinine levels, indicative of protection against hepatic, pancreatic and renal dysfunction. Pro-inflammatory mediator (TNF-α, IL-1β, IFN-γ, GCSF, GM-CSF, eotaxin, KC, MIP-1-α and IL-3, 6 and 12) levels as well as the levels of several mediators that are generally considered anti-inflammatory (IL-4, 10 and 13) were reduced by olaparib. Plasma troponin-I levels (an indicator of skeletal muscle damage) was also attenuated by olaparib. Finally, olaparib stimulated wound healing. CONCLUSIONS AND IMPLICATIONSThe clinically approved PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in murine burn injury. The data raise the potential utility of olaparib for severe burn injury.

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“…Impaired vasculogenesis is widely recognized to be a key contributor to delayed wound healing (Ruzehaji et al 2014, Zhou et al 2017. We, therefore, next investigated the angiogenic function of netrin-1 in HUVECs stimulated with high glucose.…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 restores cell injury and impaired angiogenesis in vascular endothelial cells upon high glucose by PI3K/AKT-eNOS

Xing

Lai

Liu

et al. 2017

Journal of Molecular Endocrinology

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Diabetic foot ulceration (DFU) represents a common vascular complication of diabetes mellitus (DM) with high morbidity and disability resulting from amputation. Netrin-1 level was decreased in type 2 DM patients and has been identified as a protective regulator against diabetes-triggered myocardial infarction and nephropathy. Unfortunately, its role and molecular mechanism in DFU remain poorly elucidated. Here, netrin-1 levels were reduced in DM and DFU patients relative to healthy controls, with netrin-1 levels being the lowest in DFU patients. Moreover, exposure to high glucose (HG) also suppressed netrin-1 expression in human umbilical vein endothelial cells (HUVECs). Elevated netrin-1 expression by infection with Ad-netrin-1 adenovirus vector protected against HUVEC injury in response to HG by ameliorating the inhibitory effects on cell viability, lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, cell apoptotic rate and caspase-3 activity. Importantly, HG-impaired angiogenesis was improved after netrin-1 overexpression by elevating cell migration, capillary-like tube formation and VEGF production. Mechanism assay substantiated that netrin-1 elevation increased the phosphorylation levels of AKT and eNOS, and NO production, which was notably suppressed by HG, indicating that netrin-1 overexpression restored HG-triggered impairment of the PI3K/AKT-eNOS pathway. More intriguingly, preconditioning with LY294002 (PI3K/AKT antagonist) or -monomethyl-l-arginine (eNOS inhibitor) antagonized netrin-1-induced activation of the PI3K/AKT-eNOS pathway. Concomitantly, treatment with these antagonists also attenuated the protective role of netrin-1 in endothelial dysfunction upon HG stimulation. These results suggest that elevation of netrin-1 may restore HG-triggered impairment of HUVEC and angiogenesis by activating the PI3K/AKT-eNOS pathway, indicating a potential agent for wound healing in DFU patients.

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Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis

Abstract: Delayed healing in ischemic and diabetic wounds is caused by PARP hyperactivity, and PARP inhibition significantly enhanced ischemic and diabetic wound healing by promoting angiogenesis.

Cited by 27 publications

References 34 publications

Rhein protects against cerebral ischemic‑/reperfusion‑induced oxidative stress and apoptosis in rats

Rhein protects against cerebral ischemic‑/reperfusion‑induced oxidative stress and apoptosis in rats

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third‐degree burn injury

Netrin-1 restores cell injury and impaired angiogenesis in vascular endothelial cells upon high glucose by PI3K/AKT-eNOS

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