Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice

Darby, Ian A.; Bisucci, Teresa; Hewitson, Tim D.; MacLellan, Donald G.

doi:10.1016/s1357-2725(96)00131-8

Cited by 183 publications

(147 citation statements)

References 27 publications

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“…The present study confirms that Type 1 diabetes causes relevant alterations in ECs within wound microvasculature, consisting of depressed proliferation and increased apoptosis [23]. Most importantly, it adds the novel information that disturbed EC biology is associated not only with low NGF content, but also with distinct expressional alterations of vascular NGF receptors resulting in a 100-fold decrease of TrkA : p75 ratio.…”

Section: Discussionsupporting

confidence: 83%

Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice

et al. 2004

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Aims/hypothesis. The neurotrophin nerve growth factor (NGF) is pro-angiogenic and facilitates wound repair. The present study was conducted to (i) assess the statement of NGF system components in diabetic wounds and (ii) evaluate whether NGF supplementation could prevent impairment of wound neoangiogenesis by diabetes. Methods. Skin wounds were produced in the interscapular region of streptozotocin-induced diabetic mice. NGF (1 µg per day in PBS) or vehicle was applied onto the ulcers for 3 days after punching. Nondiabetic mice were used as controls.Results. In wounds of untreated diabetic mice, endogenous levels of immunoreactive NGF were lower than those in wounds of non-diabetic mice (p<0.01). Immunohistochemical analysis showed down-regulation of tyrosine kinase receptor-A (TrkA) and up-regulation of p75 receptor in granulation tissue microvasculature. Local NFG administration prevented diabetesinduced expressional alterations, enhanced reparative capillarisation (p<0.01), and accelerated wound closure (p<0.01). This was associated with a three-fold increase in endothelial cell proliferation (p<0.01), while apoptosis was reduced by 50% (p<0.05). Quantitative RT-PCR documented a 5.5-fold increase in the expression of vascular endothelial growth factor-A (VEGF-A) by exogenous NGF in diabetic tissues (p<0.01). In in vitro preparations of human endothelial cells from derma, NGF increased the release of immunoreactive VEGF-A, and reduced high-glucose-induced apoptosis (p<0.05), the latter effect being inhibited by a VEGF-A receptor-2 antagonist. Conclusions/interpretation. Diabetic ulcers display distinct alterations in reparative angiogenesis and in the expression of NGF and its receptors. NGF supplementation corrects endogenous liabilities, facilitates vascular regeneration, and suppresses endothelial apoptosis seemingly via VEGF-A. Our findings unravel new mechanisms responsible for NGF reparative action.

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Section: Discussionsupporting

confidence: 83%

Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice

et al. 2004

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“…Procollagen-8␣ mRNA was decreased in the diabetic group, as was reported in a study of a diabetes-induced model of impaired wound healing (38). The mRNA for MARCKS (myristoylated alanine-rich protein kinase C substrate) protein was also decreased in diabetes.…”

Section: Resultssupporting

confidence: 77%

Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice

Yechoor

Patti

Saccone

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

143

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Metabolic abnormalities underlying diabetes are primarily the result of the lack of adequate insulin action and the associated changes in protein phosphorylation and gene expression. To define the full set of alterations in gene expression in skeletal muscle caused by diabetes and the loss of insulin action, we have used Affymetrix oligonucleotide microarrays and streptozotocindiabetic mice. Of the genes studied, 235 were identified as changed in diabetes, with 129 genes up-regulated and 106 down-regulated. Analysis revealed a coordinated regulation at key steps in glucose and lipid metabolism, mitochondrial electron transport, transcriptional regulation, and protein trafficking. mRNAs for all of the enzymes of the fatty acid ␤-oxidation pathway were increased, whereas those for GLUT4, hexokinase II, the E1 component of the pyruvate dehydrogenase complex, and subunits of all four complexes of the mitochondrial electron transport chain were all coordinately down-regulated. Only about half of the alterations in gene expression in diabetic mice could be corrected toward normal after 3 days of insulin treatment and euglycemia. These data point to as of yet undefined mechanisms for highly coordinated regulation of gene expression by insulin and potential new targets for therapy of diabetes mellitus.

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“…Studies in soft tissue wounds indicate that diabetic mice have increased levels of apoptosis, which may interfere with the capacity for wound healing (11,32,46). Thus, diabetes may have a general effect of increasing apoptosis of matrix producing cells, which limits the repair of injured hard or soft connective tissue.…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Alikhani

Boyd

et al. 2007

Bone

321

220

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We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation endproducts (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen) was injected in vivo and stimulated a 5 fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC-3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2 and 4.4 fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P<0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-κB activation. When osteoblastic cells were exposed to a long-term low dose incubation with CMLcollagen there was a higher degree of apoptosis compared to short term incubation. In more differentiated osteoblastic cultures apoptosis was enhanced even further. These results indicate that advanced glycation endproducts, which accumulate in diabetic and aged individuals may promote apoptosis of osteoblastic cells and contribute to deficient bone formation.

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Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice

Cited by 183 publications

References 27 publications

Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice

Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice

Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

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