Role of ADP‐ribosylation in wound repair. The contributions of Thomas K. Hunt, MD

Ghani, Q. Perveen; Wagner, Silvia; Hussain, Mansoor

doi:10.1046/j.1524-475x.2003.11608.x

Cited by 33 publications

(32 citation statements)

References 43 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ghani proposed a role for LDH and lactate in collagen production upon noting that oxamate abrogates the effects of lactate in cultured cells (14). ADPribose (ADPR) monomer binds to and inhibits collagen prolyl hydroxylase, and increased lactate decreases ADPribosylation and enhances collagen hydroxylation and deposition.…”

Section: Discussionmentioning

confidence: 99%

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Hunt

Aslam

Beckert

et al. 2007

Antioxidants & Redox Signaling

Self Cite

209

177

View full text Add to dashboard Cite

Hypoxia serves as a physiological cue to drive angiogenic response via HIF-dependent mechanisms. Interestingly, minor elevation of lactate levels in the tissue produces the same effect under aerobic conditions. Aerobic glycolysis contributes to lactate accumulation in the presence of oxygen especially under inflammatory conditions. We have previously postulated that aerobic lactate accumulation, already known to stimulate collagen deposition, will also stimulate angiogenesis. If substantiated, this concept would advance understanding of wound healing and aerobic angiogenesis because lactate accumulation has many aerobic sources. In this study, Matrigel® plugs containing a powdered, hydrolysable lactate polymer were implanted into the subcutaneous space of mice. Lactate monomer concentrations in the implant were consistent with wound levels for over 11 days. They induced little inflammation but considerable VEGF production and were highly angiogenic as opposed to controls. Arterial hypoxia abrogated angiogenesis. Furthermore, inhibition of lactate dehydrogenase using oxamate also prevented the angiogenic effects of lactate. Lactate monomer, at concentrations found in cutaneous wounds, stabilized HIF-1α and increased VEGF levels in aerobically cultured human endothelial cells. Accumulated lactate, therefore, appears to convey the impression of "metabolic need" for vascularization even in well-oxygenated and pH-neutral conditions. Lactate and oxygen both stimulate angiogenesis and matrix deposition.

show abstract

Section: Discussionmentioning

confidence: 99%

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Hunt

Aslam

Beckert

et al. 2007

Antioxidants & Redox Signaling

Self Cite

209

177

View full text Add to dashboard Cite

show abstract

“…In particular, high lactate levels were found to be associated with a high incidence of distant metastases already in early stages of the disease and inversely, longer survival was associated with low lactate concentrations in tumors. Among the possible mechanisms supporting these clinical data, lactate is proposed to stimulate angiogenesis (14)(15)(16)(17) through an activation of the VEGF/VEGFR2 signaling pathway (18)(19)(20); a parallel lactate-induced TGFb-1-mediated pathway was also proposed to prevent maturation of neoformed tubes (21). Because of the known HIF-mediated regulation of VEGF (22) and the capacity of glycolytic carboxylate intermediates including pyruvate and lactate to stimulate hypoxia-inducible factor (HIF) expression (23,24), the effects of lactate on VEGF (and angiogenesis in general) are thought to be HIF-1a-dependent (16).…”

Section: Introductionmentioning

confidence: 99%

Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis

et al. 2011

View full text Add to dashboard Cite

Lactate generated from pyruvate fuels production of intracellular NAD þ as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IkBa, and then stimulate an autocrine NF-kB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8-targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8-dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NFkB/IL-8 pathway as an important link between tumor metabolism and angiogenesis. Cancer Res; 71(7); 2550-60. Ó2011 AACR.

show abstract

“…In both wounds and tumors, the local tissue lactate concentration is elevated and reaches ϳ6 to 15 mM, in contrast to a concentration of 1.8 to 2 mM under normal physiological conditions (14,53). Lactate has been reported to be proangiogenic, and substantial attention has been focused on endothelial cell responses in wounds and tumors (10,13). Whether lactate plays a direct role in vasculogenesis, that is, homing and vascular channel formation by stem/progenitor cells (SPCs), however, is unknown.…”

mentioning

confidence: 99%

“…Lactate and pyruvate are interconvertible via the enzymatic action of LDH. Both can stabilize HIF-1 by oxidizing cellular iron, which inhibits prolyl hydroxylase activity that requires ferrous iron (10,13,32).…”

mentioning

confidence: 99%

Lactate Stimulates Vasculogenic Stem Cells via the Thioredoxin System and Engages an Autocrine Activation Loop Involving Hypoxia-Inducible Factor 1

Milovanova

Bhopale

Sorokina

et al. 2008

Molecular and Cellular Biology

View full text Add to dashboard Cite

The recruitment and differentiation of circulating stem/progenitor cells (SPCs) in subcutaneous Matrigel in mice was assessed. There were over one million CD34؉ SPCs per Matrigel plug 18 h after Matrigel implantation, and including a polymer to elevate the lactate concentration increased the number of SPCs by 3.6-fold. Intricate CD34؉ cell-lined channels were linked to the systemic circulation, and lactate accelerated cell differentiation as evaluated based on surface marker expression and cell cycle entry. CD34؉ SPCs from lactate-supplemented Matrigel exhibited significantly higher concentrations of thioredoxin 1 (Trx1) and hypoxia-inducible factor 1 (HIF-1) than cells from unsupplemented Matrigel, whereas Trx1 and HIF-1 in CD45؉ leukocytes were not elevated by lactate. Results obtained using small inhibitory RNA (siRNA) specific to HIF-1 and mice with conditionally HIF-1 null myeloid cells indicated that SPC recruitment and lactatemediated effects were dependent on HIF-1. Cells from lactate-supplemented Matrigel had higher concentrations of phosphorylated extracellular signal-regulated kinases 1 and 2, Trx1, Trx reductase (TrxR), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1) than cells from unsupplemented Matrigel. SPC recruitment and protein changes were inhibited by siRNA specific to lactate dehydrogenase, TrxR, or HIF-1 and by oxamate, apocynin, U0126, N-acetylcysteine, dithioerythritol, and antibodies to VEGF or SDF-1. Oxidative stress from lactate metabolism by SPCs accelerated further SPC recruitment and differentiation through Trx1-mediated elevations in HIF-1 levels and the subsequent synthesis of HIF-1-dependent growth factors.

show abstract

Role of ADP‐ribosylation in wound repair. The contributions of Thomas K. Hunt, MD

Cited by 33 publications

References 43 publications

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis

Lactate Stimulates Vasculogenic Stem Cells via the Thioredoxin System and Engages an Autocrine Activation Loop Involving Hypoxia-Inducible Factor 1

Contact Info

Product

Resources

About